Inherently radiopaque polymeric products for embolotherapy

ABSTRACT

Preferred embodiments relate to compositions of inherently radiopaque, biocompatible, bioresorbable polymeric particles and methods of using them for embolizing a body lumen.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of U.S. patent application Ser.No. 15/714,302 filed Sep. 25, 2017, which is a divisional of U.S. patentapplication Ser. No. 14/197,679 filed Mar. 5, 2014, now U.S. Pat. No.9,770,465, which is a divisional of Ser. No. 10/952,274 filed Sep. 27,2004, now U.S. Pat. No. 8,685,367, which claims the benefit of priorityunder 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/601,677filed Aug. 13, 2004 and U.S. Provisional Application No. 60/505,951filed Sep. 25, 2003. The entire disclosures of the applications notedabove are incorporated herein by reference.

FIELD OF INVENTION

Preferred embodiments of the present invention relate to inherentlyradiopaque, biocompatible, bioresorbable polymeric particles and methodsof using them for embolizing a body lumen.

BACKGROUND

Embolotherapy devices and reagents include metal embolic coils, gelfoams, glues, oils, alcohol or particulate polymeric embolic agentsused, for example, to control bleeding, prevent blood loss prior to orduring a surgical procedure, restrict or block blood supply to tumorsand vascular malformations, e.g., for uterine fibroids, tumors (i.e.,chemo-embolization), hemorrhage (e.g., during trauma with bleeding) andarteriovenous malformations, fistulas and aneurysms. Embolic coils andparticles are the most commonly used.

Conventional embolic coils are generally coiled metal strands that areconstrained to a linear configuration during delivery through a vascularcatheter. They have a geometrically pre-formed ‘coiled’ state to whichthey recover upon exiting the delivery catheter. There are a number ofdifferent design and procedural variations used with metal coils (seee.g., U.S. Pat. Nos. 6,358,228 and 6,117,157); however, metal emboliccoils are designed to exploit the first response, i.e., a blood clot dueto the hemodynamic response of a physical obstruction in the blood flowand in some cases an additional response i.e., a blood clot due to thebiological response of the body to the coil material, wherein thetherapeutic goal of the blocking the blood flow is accomplished by clotformation within and around the metal coil.

Although metal embolic coils have some advantageous physicomechanicalproperties, such as inherent radiopacity and shape memory (i.e., returnto the preformed coiled state upon deployment), there are a number ofdisadvantages associated with the use of metal embolic coils, includinginter alia, chronic tissue damage, tissue hyperplasia, vessel occlusionand permanent incorporation into the tissue at the deployment site.

Non-metallic alternatives include liquid and particulate embolic agents.However, these also have significant disadvantages. Liquid embolicagents are generally divided into precipitative and reactive systems. Inthe former case, a polymer is solvated within a biologically acceptablesolvent that dissipates upon vascular delivery leaving the polymer toprecipitate in situ (see e.g., U.S. Pat. No. 5,851,508). Such agents maynot precipitate quickly enough, thereby allowing a non-solidified(viscous) polymer embolic to migrate and embolize unintended tissues.This is of particular concern with arterio-venous malformations whereinthe material can easily enter the venous system and cause a significantpulmonary embolism. Another disadvantage is the use of solvents, such asdimethylsulfoxide, for delivering the precipitative polymers.

Reactive embolic agents are primarily variations of cyanoacrylatechemical systems. An example of an FDA approved system is the TRUFILL®cyanoacrylate embolic from Cordis. Here, a liquid monomeric and/oroligomeric cyanoacrylate mixture is introduced to the vascular sitethrough a catheter wherein polymerization is initiated by the availablewater in the blood. Unfortunately, if the dwell time during delivery istoo great, the cyanoacrylate adhesive may bond the catheter tip to thetissues with grave consequences. A secondary concern is that thebioresorbable degradation products from these materials includeformaldehyde, a toxic chemical.

Particulate therapeutic emboli are composed of particles of varioussize, geometry and composition. Schwarz et al., J. Biomater., 25(21),5209-15 (2004) disclosed degradable hydroxy-ethyl acrylate (HEA)microspheres have been synthesized and tested in animals but none havebeen commercialized. The particles used for clinical applications aretypically suspended in a radiopaque contrast solution and deliveredthrough a vascular catheter via syringe injection. The three most commonparticulate embolic agents currently being used are GELFOAM® (absorbablegelatin particles from Pharmacia & Upjohn), polyvinyl alcohol (PVA) foamand trisacryl gelatin microspheres (EMBOSPHERE® from Biosphere Medical).

Unlike metallic coils, these embolics are not inherently radiopaque.Indeed, placement visualization is dependent upon inference fromfluoroscopic flow analysis during the embolic procedure. There is nodirect ability to visualize the actual particles once inside the body.Also, in the case of PVA and EMBOSPHERE, the material may reside in thebody throughout the patient's lifetime providing an increased risk ofbiological rejection. In the case of GELFOAM, there is the possibilityof tissue rejection of this animal derived agent.

Particulate embolic agents may be used, for example, to restrict orblock blood supply as in traditional applications which generallyinclude delivery through a guide catheter such as treatment of tumorsand vascular malformations, e.g., for uterine fibroids, cancerous tumors(i.e., chemo-embolization), hemorrhage (e.g., during trauma withbleeding) and arteriovenous malformations, fistulas and aneurysms.

Biocompatible, bioresorbable particulate embolic agents have thepotential advantage of being temporary. The effective removal of theparticulate foreign body over time allows the tissue to return to itsunaffected state.

Radiopaque embolic particulate agents have the potential distinctadvantage of being visible during and after embolic therapy procedures.During the procedure, visualization of the particulate agent would allowthe physician to affect precise delivery to the targeted vessel ortissue. That is, the physician would be able to ensure that theparticles do not become resident in unintended sites. This level ofcontrol would greatly enhance the safety and effectiveness ofembolotherapy. Once the radiopaque particles have been implanted,follow-up procedures could be limited to non-interventional methods,e.g., simple X-Ray radiography. In the case of a tumor, for example, itssize could be tracked since the radiopaque embolized sections would beshown converge as the mass/volume decreased with time.

As noted, biocompatible embolic particles exist on the market today.Indeed, bioresorbable biocompatible embolic agents are available in theform of GELFOAM®. As noted, however, there is a potential for rejectiondue to the animal origin of this material. Furthermore, GELFOAM® is notan FDA approved device for this application.

Attempts have been made to produce a more biocompatible degradableembolic particulate agent. Likewise, investigational radiopaque embolicagents have been produced and tested in animals for their potentialutility. In all cases external agents such as iodinated contrast mediaor a metal or its salt (e.g., tungsten, barium sulfate, etc) must beadded or inherent radiopacity imparted by halogenation ofnon-bioresorbable compositions.

Heretofore however, biocompatible, bioresorbable, inherently radiopaqueparticles for embolotherapy have not been conceived nor attempted.Accordingly, there remains an important unmet need to developbiocompatible, bioresorbable, inherently radiopaque particles forembolotherapy, which may also allow for repeat treatment of the samesite, while circumventing or alleviating the foregoing disadvantages ofexisting or conceived particulate embolic agents.

Accordingly, there remains an important unmet need to developbioresorbable, radiopaque embolic agents, wherein the polymericmaterials used to fabricate these agents have the desirable qualities ofmetal (e.g., radiopacity), while circumventing or alleviating theforegoing disadvantages associated with the use of metal coils or liquidand particulate embolic alternatives.

SUMMARY OF THE INVENTION

An embolotherapy product is disclosed in accordance with preferredembodiments of the present invention. The embolotherapy productcomprises a particulate formulation comprising a biocompatible,bioresorbable polymer, and optionally including the stereoisomersthereof, wherein the polymer comprises a sufficient number of halogenatoms to render the embolotherapy product inherently radiopaque. In somepreferred embodiments, the polymer comprises a homopolymer, aheteropolymer, or a blend thereof.

In one preferred embodiment of the embolotherapy product, the polymercomprises one or more units described by Formula I:

wherein X═I or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4;

wherein f is between 0 and less than 1; g is between 0 and 1, inclusive;and f+g is between 0 and 1, inclusive;

wherein A is either:

wherein R₁ is independently an H or an alkyl group ranging from 1 toabout 18 carbon atoms containing from 0 to 5 heteroatoms selected from Oand N;

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 8 heteroatoms selected from O and N;

wherein B is an aliphatic linear or branched diol or a poly(alkyleneglycol) unit; and

wherein R and R₂ may be independently selected from:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂-)a; wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n; wherein a and n are independentlybetween 0 and 8 inclusive; J₁ and J₂ are independently Br or I; and, forR₂, Q comprises a free carboxylic acid group, and, for R, Q is selectedfrom the group consisting of hydrogen and carboxylic acid esters andamides, wherein said esters and amides are selected from the groupconsisting of esters and amides of alkyl and alkylaryl groups containingup to 18 carbon atoms and esters and amides of biologically andpharmaceutically active compounds.

In a variation to this embodiment of Formula I, R and R₂ may be selectedfrom the groups:

wherein R₁ in each R₂ is independently an alkyl group ranging from 1 toabout 18 carbon atoms containing from 0 to 5 heteroatoms selected from Oand N and R₁ in each R is H;

wherein j and m are independently integers from 1 to 8 inclusive; and

wherein Z is independently either O or S.

In another preferred embodiment of the embolotherapy product, thepolymer may comprise one or more units described by Formula II:

wherein X for each polymer unit is independently Br or I, Y is between 1and 4, inclusive and R₄ is an alkyl, aryl or alkylaryl group with up to18 carbon atoms and from 0 to 8 heteroatoms selected from O and N.

In variations to the polymer of Formula II, all X groups may beortho-directed and Y may be 1 or 2. In another variation, R₄ is an alkylgroup.

In another variation, R₄ has the structure:

wherein R₉ for each unit is independently an alkyl, aryl or alkylarylgroup containing up to 18 carbon atoms and from 0 to 8 heteroatomsselected from O and N; and R₅ and R₆ are each independently selectedfrom hydrogen and alkyl groups having up to 18 carbon atoms and from 0to 8 heteroatoms selected from O and N.

In another variation to R₄ in Formula II, R₉ for at least one unitcomprises a pendant COOR₁ group, wherein, for each unit in which it ispresent, the subgroup R₁ is independently a hydrogen or an alkyl groupranging from 1 to about 18 carbon atoms containing from 0 to 5heteroatoms selected from O and N.

In another variation to R₄ in Formula II, R₉ independently has thestructure:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂-)a, wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n, wherein a and n are independentlybetween 0 and 8 inclusive; and J₁ and J₂ are independently Br or I; andQ is selected from the group consisting of hydrogen, a free carboxylicacid group, and carboxylic acid esters and amides, wherein said estersand amides are selected from the group consisting of esters and amidesof alkyl and alkylaryl groups containing up to 18 carbon atoms andesters and amides of biologically and pharmaceutically active compounds.

In another variation to R₄ in Formula II, R₉ independently has thestructure:

wherein R_(5a) is an alkyl group containing up to 18 carbon atoms andfrom 0 to 5 heteroatoms selected from O and N; and wherein m is aninteger from 1 to 8 inclusive; and R₁ is independently a hydrogen or analkyl group ranging from 1 to about 18 carbon atoms containing from 0 to5 heteroatoms selected from O and N.

In another variation to R₄ in Formula II, R₉ independently has thestructure:

wherein j and m are independently an integer from 1 to 8, inclusive, andR₁ is independently a hydrogen or an alkyl group ranging from 1 to about18 carbon atoms containing from 0 to 5 heteroatoms selected from O andN.

In some embodiments of the embolotherapy products of the presentinvention, the polymer may be copolymerized with a poly(C₁-C₄ alkyleneglycol). Preferably, the poly(C₁-C₄ alkylene glycol) is present in aweight fraction of less than about 75 wt %. More preferably, thepoly(alkylene glycol) is poly(ethylene glycol).

In another variation to the polymers disclosed herein, between about0.01 and about 0.99 percent of said polymer units comprise a pendant—COOH group.

In another variation to Formula II, R₄ may be an aryl or alkylarylgroup. Preferably, the R₄ aryl or alkylaryl group is selected so thatthe polymer units are diphenols.

In another preferred embodiment of the embolotherapy product, thepolymer may comprise one or more units described by Formula III:

wherein X for each polymer unit is independently Br or I, Y1 and Y2 areeach independently between 0 and 4, inclusive, Y1+Y2 for each unit isindependently between 1 and 8, inclusive, and R₂ for each polymer unitis independently an alkyl, aryl or alkylaryl group containing up to 18carbon atoms and from 0 to 8 heteroatoms selected from O and N.

In preferred variations to Formula III, all X groups are ortho-directed.Preferrably, Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or4.

In another variation to Formula III, R₂ for at least one unit maycomprise a pendant COOR₁ group, wherein, for each unit in which theCOOR₁ group is present, the subgroup R₁ is independently a hydrogen oran alkyl group ranging from 1 to about 18 carbon atoms containing from 0to 5 heteroatoms selected from O and N.

In another variation to Formula III, R₂ independently has the structure:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂-)a, wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n, wherein a and n are independentlybetween 0 and 8 inclusive; and J₁ and J₂ are independently Br or I; andQ is selected from the group consisting of hydrogen, a free carboxylicacid group, and carboxylic acid esters and amides, wherein said estersand amides are selected from the group consisting of esters and amidesof alkyl and alkylaryl groups containing up to 18 carbon atoms andesters and amides of biologically and pharmaceutically active compounds.

In another variation to Formula III, R₂ independently has the structure:

wherein R_(5a) is an alkyl group containing up to 18 carbon atoms andfrom 0 to 5 heteroatoms selected from O and N; and wherein m is aninteger from 1 to 8 inclusive; and R₁ is independently a hydrogen or analkyl group ranging from 1 to about 18 carbon atoms containing from 0 to5 heteroatoms selected from O and N.

In another variation to Formula III, R₂ independently has the structure:

wherein j and m are independently an integer from 1 to 8, inclusive, andR₁ is independently a hydrogen or an alkyl group ranging from 1 to about18 carbon atoms containing from 0 to 5 heteroatoms selected from O andN.

In a preferred variation to Formula III, between about 0.01 and about0.99 percent of the polymer units comprise a pendant COOH group.Preferably, the polymer is copolymerized with up to 75 wt % of apoly(C₁-C₄ alkylene glycol). More preferably, the poly(C₁-C₄ alkyleneglycol) is poly(ethylene glycol).

In another preferred embodiment of the embolotherapy product, thepolymer may comprise one or more units described by Formula IV:

wherein each X is independently I or Br, Y1 and Y2 for each diphenolunit are independently between 0 and 4, inclusive, and Y1+Y2 for eachdiphenol unit is between 1 and 8, inclusive;

each R and R₂ are independently an alkyl, aryl or alkylaryl groupcontaining up to 18 carbon atoms and from 0 to 8 heteroatoms selectedfrom O and N, wherein R₂ further comprises a pendant carboxylic acidgroup;

wherein A is either:

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 8 heteroatoms selected from O and N;

P is a poly(C₁-C₄ alkylene glycol) unit having a weight fraction ofabout 75% or less; f is between 0 and less than 1, g is between 0 and 1,inclusive; and f+g is between 0 and 1, inclusive.

In preferred variations to Formula IV, P is a poly(ethylene glycol) thatis present in a weight fraction of about 50% or less. More preferably, Pis a poly(ethylene glycol) that is present in a weight fraction of about30% or less.

In other preferred variations to Formula IV, both R and R₂ comprise apendant COOR₁ group; wherein for R, the subgroup R₁ is independently analkyl group ranging from 1 to about 18 carbon atoms containing from 0 to5 heteroatoms selected from O and N; and wherein for R₂, the subgroup R₁is a hydrogen atom.

In other preferred variations to Formula IV, each R and R₂ independentlyhas the structure:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂-)a, wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n, wherein a and n are independentlybetween 0 and 8 inclusive; and J₁ and J₂ are independently Br or I; andQ for R₂ comprises a free carboxylic acid group, and Q for each R isindependently selected from the group consisting of hydrogen, carboxylicacid esters and amides, wherein said esters and amides are selected fromthe group consisting of esters and amides of alkyl and alkylaryl groupscontaining up to 18 carbon atoms and esters and amides of biologicallyand pharmaceutically active compounds.

In other preferred variations to Formula IV, each R₂ independently hasthe structure:

wherein R_(5a) is an alkyl group containing up to 18 carbon atoms andfrom 0 to 5 heteroatoms selected from O and N; and wherein m is aninteger from 1 to 8 inclusive; and R₁ is a hydrogen.

In other preferred variations to Formula IV, each R₂ independently hasthe structure:

wherein j and m are independently an integer from 1 to 8, inclusive, andR₁ is a hydrogen. Preferably, each carboxylic acid ester or amide for Ris either an ethyl or a butyl ester or amide.

In other preferred variations to Formula IV, A is a —C(═O)— group. Inanother preferred variation to Formula III, A is:

wherein R₃ is a C₄-C₁₂ alkyl, C₈-C₁₄ aryl, or C₈-C₁₄ alkylaryl.Preferably, R₃ is selected so that A is a moiety of a dicarboxylic acidthat is a naturally occurring metabolite. More preferably, R₃ is amoiety selected from —CH₂—C(═O)—, —CH₂—CH₂—C(═O)—, —CH═CH— and(—CH₂-)_(z), wherein z is an integer from 1 to 8, inclusive.

In other preferred variations to Formula IV, all X groups areortho-directed. Preferably, Y1 and Y2 are independently 2 or less, andY1+Y2=1, 2, 3 or 4.

In other preferred variations to Formula IV, every halogen is iodine.

In other preferred variations to Formula IV, f is greater than 0.1 toabout 0.3. Preferably, f is greater than 0.2 to about 0.25.

In other preferred variations to Formula IV, the poly(C₁-C₄ alkyleneglycol) weight fraction is less than about 25 wt %.

In other preferred variations to Formula IV, g is greater than 0.1 toabout 0.35. More preferably, g is greater than 0.2 to about 0.3.

In another preferred embodiment of the embolotherapy product, thepolymer may comprise one or more units described by Formula V:

wherein each X is independently iodine or bromine; each y isindependently between 0 and 4, inclusive, wherein a total number ofring-substituted iodine and bromine is between 1 and 8, inclusive; eachR₄ and R₆ are independently an alkyl, aryl or alkylaryl group containingup to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N,and R₄ further includes a pendant carboxylic acid group;

wherein A is either:

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 5 heteroatoms selected from the group consisting of O and N;

P is a poly(C₁-C₄ alkylene glycol) unit present in a weight fraction ofless than about 75 wt %;

f is from greater than 0 to less than 1; g is between 0 and 1,inclusive; and f+g is between 0 and 1, inclusive.

Preferably, P is a poly(ethylene glycol) unit.

In preferred variations to Formula V, each R₄ and R₆ of said polymercontains a pendant —COOR₁ group, wherein for each R₆, each subgroup R₁is independently an alkyl group ranging from 1 to about 18 carbon atomscontaining from 0 to 5 heteroatoms selected from the group consisting ofO and N, and, for each R₄, each subgroup R₁ is a hydrogen atom.

In other preferred variations to Formula V, each R₄ and R₆ of saidpolymer are:

wherein R_(5a) is an alkyl group containing up to 18 carbon atoms andfrom 0 to 5 heteroatoms selected from O and N; and wherein m is aninteger from 1 to 8 inclusive; and for each R₆, each subgroup R₁ isindependently an alkyl group ranging from 1 to about 18 carbon atomscontaining from 0 to 5 heteroatoms selected from O and N, and, for eachR₄, each subgroup R₁ is a hydrogen atom.

In other preferred variations to Formula V, each R₁ subgroup for R₆ ofsaid polymer is either ethyl or butyl.

In other preferred variations to Formula V, A is a —C(═O)— group.Alternatively, A may be:

wherein R₃ is C₄-C₁₂ alkyl, C₈-C₁₄ aryl, or C₈-C₁₄ alkylaryl.

In other preferred variations to Formula V, R₃ is selected so that A isa moiety of a dicarboxylic acid that is a naturally occurringmetabolite.

In other preferred variations to Formula V, R₃ is a moiety selected fromthe group consisting of —CH₂—C(═O)—, —CH₂—CH₂—C(═O)—, —CH═CH— and(—CH₂-)z, wherein z is an integer from 1 to 8, inclusive.

In other preferred variations to Formula V, all X groups areortho-directed and y is 2 or 3.

In other preferred variations to Formula V, every X group is iodine.

In other preferred variations to Formula V, f is greater than 0.1 toabout 0.3.

In other preferred variations to Formula V, g is greater than 0.1 toabout 0.35.

In preferred embodiments of the embolotherapy product of the presentinvention, the particulate formulation may be configured foradministration via injection. The formulation may comprises polymerparticles selected from the group consisting of spherical particles,geometrically non-uniform particles, porous particles, hollow particles,solid particles, and particles having an excluded diameter of from about10 microns to about 5,000 microns, and combinations thereof.

Alternatively, the formulation may comprise a polymer hydrogelcomposition.

In a preferred embodiment of the embolotherapy product, the polymer mayfurther comprise an effective amount of at least one therapeutic agent.Preferably, the at least one therapeutic agent is selected from thegroup consisting of a chemotherapeutic agent, a non-steroidalanti-inflammatory, or a steroidal anti-inflammatory.

In another preferred embodiment of the embolotherapy product, thepolymer may further comprise an effective amount of a magnetic resonanceenhancing agent.

In a preferred embodiment of the embolotherapy product, the polymer mayfurther comprise an effective amount of a radiopacifying agent, selectedfrom the group consisting of iodine, bromine, barium, bismuth, gold,platinum, tantalum, tungsten, and mixtures thereof.

In another preferred embodiment of the embolotherapy product, thepolymer may further comprise a biocompatible, bioresorbable polymericcoating adapted to promote a selected biological response. Preferably,the biological response is selected from the group consisting ofthrombosis, cell attachment, cell proliferation, attraction ofinflammatory cells, and deposition of matrix proteins, inhibition ofthrombosis, inhibition of cell attachment, inhibition of cellproliferation, inhibition of inflammatory cells, and inhibition ofdeposition of matrix proteins or a combination thereof.

In another preferred embodiment of the embolotherapy product, thepolymer may comprise Formula I:

wherein X═I or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4;

wherein f is between 0 and less than 1; g is between 0 and 1, inclusive;and f+g is between 0 and 1, inclusive;

wherein R and R₂ may be independently selected from:

wherein, for R₂, R₁ is H and for R, R₁ is a long chain aliphatichydrocarbon;

wherein j and m are independently integers from 1 to 8 inclusive;

wherein Z is independently either O or S;

wherein A is selected from the group consisting of:

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 8 heteroatoms selected from O and N; and

wherein B is an aliphatic linear or branched diol, or a poly(alkyleneglycol) unit.

A method for embolizing a body lumen is disclosed in accordance withanother preferred embodiment of the present invention. The methodcomprises the step of introducing into the body lumen an effectiveamount of an embolotherapy product comprising a particulate formulationcomprising a biocompatible, bioresorbable polymer, wherein the polymercomprises a sufficient number of halogen atoms to render theembolotherapy product inherently radiopaque.

Preferably, the step of introducing is accomplished by injection viaeither a catheter or syringe.

In another preferred embodiment of the present invention, a method oftreating varicose and/or spider veins is disclosed. The method comprisesadministering within said varicose and/or spider veins an effectiveamount of an embolotherapy product comprising a particulate formulationcomprising a biocompatible, bioresorbable polymer, wherein the polymercomprises a sufficient number of halogen atoms to render theembolotherapy product inherently radiopaque.

Preferably, the step of administering is accomplished by injection viaeither a catheter or syringe.

A method for enhancing the local delivery of a therapeutic agent to atissue is also disclosed in accordance with preferred embodiments of thepresent invention. The method comprises the steps of: administering to ablood vessel associated with the tissue an amount of an embolotherapyproduct sufficient to reduce the blood flow from said tissue;administering the therapeutic agent to the blood vessel separately or incombination with the embolotherapy product, such that the local deliveryof the therapeutic agent is enhanced; and repeating the steps ofadministering the embolotherapy product and therapeutic agent after theembolotherapy product first administered has degraded sufficiently toallow for re-access to said blood vessel. The embolotherapy product foruse in this method comprises a particulate formulation comprising abiocompatible, bioresorbable polymer, wherein the polymer comprises asufficient number of halogen atoms to render the embolotherapy productinherently radiopaque.

A method for re-treatment of a body lumen is also disclosed. The methodcomprises the steps of: administering to a region of a blood vesselassociated with said tissue an amount of a biocompatible, bioresorbablepolymeric embolotherapy product sufficient to reduce the blood flow fromthe tissue for a period of time; and administering at a later time anyembolotherapy product, to the same approximate region of the bloodvessel associated with said tissue such that the said tissue may bere-treated or allow for other forms of re-intervention.

In one embodiment of the embolotherapy product of the present invention,the polymer comprises a bioresorbable inherently radiopaque polymer thatis not naturally occurring. In another variation, the polymer comprisesa bioresorbable inherently radiopaque polymer comprising at least oneamino acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A, FIG. 1B and FIG. 1C depict x-ray views of an explanted porcinekidney injected with a radiopaque polymeric embolotherapy compositionaccording to preferred embodiments.

FIG. 2 depicts dissolution of an example chemotherapeutic drug(Paclitaxel) out of poly-DTE-carbonate coating, a biocompatiblepolymeric embolotherapy coating, according to preferred embodiments intoPBS with Tween 20 at 37° C.

FIG. 3A and FIG. 3B depicts an X-ray comparison of a radiopaquebioresorbable tri-iodinated tyrosine-derived polycarbonate films showingthe radiopacity according to one preferred embodiment of the presentinvention. The poly(I2DITE-co-20%PEG2k) carbonate films have aphoto-density equivalent to human bone.

BEST MODES OF CARRYING OUT THE INVENTION

Bioresorbable, inherently radiopaque polymeric embolotherapy productsare disclosed in accordance with preferred embodiments of the presentinvention. They may be used, for example, to temporarily restrict orblock blood supply as in traditional applications which generallyinclude delivery through a catheter such as treatment of tumors andvascular malformations, e.g., for uterine fibroids, tumors (i.e.,chemo-embolization), hemorrhage (e.g., during trauma with bleeding) andarteriovenous malformations, fistulas and aneurysms. Further theseembolic agents may be delivered by other means, for example, directlyinto the body through a syringe or other non-catheter vehicle to providecosmetic treatment for spider veins (unattractive or undesirable small,veins close to the skin surface that are tree branch-shaped or spiderweb-shaped and red or blue in color) found on both the legs and the faceor even varicose veins (swollen and raised above the surface of theskin).

Embolotherapy products according to preferred aspects of the presentinvention can have at least some of the following attributes: (a)sufficient radiopacity to be visible by conventional X-ray fluoroscopy,(b) sufficient particle compressibility, flow and buoyancy attributes tofabricate embolotherapy delivery and functionality; (c) desirablesurface properties or functionalities that can be adjusted to accountfor the needs (e.g., blood compatibility or thrombosis) for a range ofapplications; (d) desirable biodegradation and bioresorption profilesthat can be adjusted to account for the needs of a range of applicationsinvolving blockage of a body lumen for different lengths of time; (e)desirable residence time in the body lumen with said tissue such that ata later time any embolic product may be used to re-treat the approximatesame region of the blood vessel and said tissue or allow for other formsof re-treatment such as surgery; (f) an amount of a therapeuticsufficient to promote a desirable biological and/or physiological effectand/or (g) a biocompatible, bioresorbable coating sufficient to promotea desirable biological and/or physiological effect of an embolized bodylumen. A body lumen is used herein to designate a vascular body lumen orblood vessel (i.e., arterial and/or venous vessel of any size) thatcomprises the body circulatory system.

According to one aspect of the present invention, an embolotherapyproduct is provided that is a particulate formulation of abiocompatible, bioresorbable polymer, wherein the polymer has asufficient number of halogen atoms to render the embolotherapy productvisible by conventional x-ray fluoroscopy.

Preferred embodiments of the present invention are directed tocompositions and methods for embolizing or occluding a body lumen,preferably a blood vessel, by introducing therein a biocompatible,bioresorbable, particulate polymeric material. In more preferredembodiments the polymeric material incorporates a radiopaque moiety,preferably, a halogen, and most preferably an iodine and/or bromine. Theterm “bioresorbable” is used herein to designate polymers that undergobiodegradation (through the action of water and/or enzymes to bechemically degraded) and at least some of the degradation products areeliminated and/or absorbed by the body. The term “radiopaque” is usedherein to designate an object or material comprising the object visibleby in vivo analysis techniques for imaging such as, but not limited to,methods such as x-ray radiography, fluoroscopy, other forms ofradiation, MRI, electromagnetic energy, structural imaging (such ascomputed or computerized tomography), and functional imaging (such asultrasonography).

Additionally, applicants have found that the halogenated polymers of thepresent invention exhibit a unique combination of properties that areparticularly beneficial for embolotherapy use, including radiopacity,biocompatibility and bioabsorbability. These polymers may include forexample, embodiments of the genus described in U.S. Pat. No. 6,475,477(incorporated herein in its entirety by reference), and moreparticularly iodinated and/or brominated biocompatible diphenols andpoly(alkylene glycols), which exhibit a unique combination of propertiesthat are particularly beneficial for embolotherapy use.

Significantly, while U.S. Pat. No. 6,475,477 describes a wide variety ofpolymers having various combinations of properties and characteristics,applicants have discovered presently that certain polymers exhibit acombination of properties that are significantly and surprisinglysuperior to those polymers disclosed in U.S. Pat. No. 6,475,477.

As used herein, an “embolotherapy product” means any polymericformulation adapted to embolize a body lumen (e.g., control bleeding,prevent blood loss, and/or restrict or block blood flow). Examplesinclude compositions such as injectable polymeric formulations,particles, hydrogels, and the like.

Embolotherapy products according to the preferred embodiments areprepared using conventional designs substituting the disclosedradiopaque, biocompatible, bioresorbable polymers for thenon-therapeutic structural materials conventionally employed. Suchproducts are inherently effective. The embolotherapy products accordingto the preferred embodiments are administered by conventional means ineffective quantities to the site to be embolized.

Applicants have discovered that a biocompatible, bioresorbable,inherently radiopaque polymer class can be produced from a broad classof aryl-containing biocompatible, bioresorbable polymers. For example,in all of the biocompatible, bioresorbable polymers noted in the TABLE 1below, radiopacity may be introduced to the aromatic rings viahalogenation, particularly bromination and iodination, by well-knowntechniques that can be readily employed by those of ordinary skill inthe art without undue experimentation. Indeed, U.S. Pat. No. 6,475,477reveals a broad class of inherently radiopaque, biocompatible,bioresorbable polymers made in this manner Radiopacity may be impartedto the monomeric components of the other polymers in this table in alike fashion.

TABLE 1 US Patent Patent Title What is taught 6,475,477 Radio-opaquepolymer Iodine- and bromine-substi- biomaterials tuted diphenol monomersynthesis Iodine- and bromine-substi- tuted polycarbonate homo- polymersand copolymer synthesis Iodine- and bromine-sub- stituted polyarylatehomo- polymers and copolymer synthesis 5,658,995 Copolymers of tyrosine-Random block copolymer based polycarbonate of a tyrosine-derived andpoly(alkylene oxide) diphenol monomer and a poly(alkylene oxide)synthesis 6,048,521 Copolymers of tyrosine- Random block copolymersbased polyarlates and of both polycarbonates and poly(alkylene oxides)polyarylates with and poly(alkylene oxides) 6,120,491 Biodegradable,anionic Synthesis of block co- polymers derived from polymers ofpolycarbonates the amino acid L-tyrosine and polyarylates having pendentcarboxylic acid groups with poly(alkylene oxides) groups in thebackbone. 6,284,862 Monomers derived from Synthesis of aliphatic-hydroxy acids and polymers aromatic dihydroxy prepared therefrommonomers and bioresorbable polymers 4,863,735 Biodegradable polymericPoly(iminocarbonate) drug delivery system with synthesis adjuvantactivity 6,238,687 Biodegradable polymers, Processes for preparingcompositions, articles phosphorus and and methods for makingdesaminotyrosyl L-tyrosine and using the same linkages in the polymerbackbone 5,912,225 Biodegradable poly Processes for preparing(phosphoester-co- polymers containing desaminotyrosyl phosphorus andL-tyrosine ester) desaminotyrosyl L-tyrosine compounds, composi-linkages tions, articles and methods for making and using the same4,638,045 Non-peptide polyamino Polymers with a plurality acidbioerodible polymers of monomer units of two or three amino acids6,602,497 Strictly alternating Polyethers with strictly poly(alkyleneoxide alternating poly(alkylene ether) copolymers oxide) and tyrosine-derived monomeric repeating units 5,198,507 Synthesis of Amino Polymerblends of the Acid-derived bio- amino acid-derived erodible polymerspolycarbonates with polyiminocarbonates prepared from identical aminoacid-derived diphenol starting materials

All of the U.S. patents recited in TABLE 1 and their methods ofpreparation are incorporated herein in their entirety by referencethereto. The polyethers of U.S. Pat. No. 6,602,497 may requirecross-linking before use in embolotherapy. However, appropriatecross-linking methods are essentially conventional and require no undueexperimentation on the part of the ordinarily skilled artisan.

The term, “ortho-directed”, is used herein to designate orientationrelative to the phenoxy alcohol group.

The term, “inherently radiopaque”, is used herein to designate polymerthat is intrinsically radiopaque due to the covalent bonding of halogenspecies to the polymer.

Accordingly, the term does not encompass a polymer, which is simplyblended with a halogenated species or other radiopacifying agents suchas metals and their complexes.

The halogenated compositional variations of the polymers in TABLE 1 maybe generically represented by the following formulas. It should be notedthat the compositional ranges noted below exceeds those described inTABLE 1.

It is understood that the presentation of the various polymer formulaerepresented may include homopolymers and heteropolymers, and also thestereoisomers thereof. Homopolymer is used herein to designate a polymercomprised of all the same type of monomers. Heteropolymer is used hereinto designate a polymer comprised of two or more different types ofmonomer, which is also called a co-polymer. A heteropolymer orco-polymer may be of a kind known as block, random and alternating.Further with respect to the presentation of the various polymerformulae, embolotherapy products according to embodiments of the presentinvention may be comprised of a homopolymer, a heteropolymer and/or ablend of such polymers.

Preferred Polymers

In accordance with one preferred embodiment of the present invention, anembolotherapy product is disclosed, comprising an inherently radiopaque,biocompatible, bioresorbable polymer, including homogeneous polymers,copolymers and blends thereof, wherein the polymer comprises one or moreof the following units (Formula I):

wherein X═I or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4;

wherein f and g can range from 0 to 1 as compositional/performancerequirements dictate, provided that f is less than 1 and f+g is between0 and 1, inclusive;

R and R₂ may be independently selected from:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂-)a, wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n, wherein a and n are independentlybetween 0 and 8 inclusive; and J₁ and J₂ are independently Br or I; andQ for each R₂ comprises a free carboxylic acid group, and Q for each Ris selected from the group consisting of hydrogen, and carboxylic acidesters and amides, wherein said esters and amides are selected from thegroup consisting of esters and amides of alkyl and alkylaryl groupscontaining up to 18 carbon atoms and esters and amides of biologicallyand pharmaceutically active compounds.

In more preferred embodiments of Formula I, R and R₂ may beindependently selected from the groups:

wherein R₁ for each R₂ is H and R₁ for each R is independently a longchain aliphatic hydrocarbon, and in some embodiments, an alkyl groupranging from 1 to about 18 carbon atoms containing from 0 to 5heteroatoms selected from O and N;

wherein j and m are independently integers from 1 to 8 inclusive;

wherein Z is independently either O or S;

A is either:

wherein R₁ is defined as previously;

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 8 heteroatoms selected from O and N; and

wherein B is an aliphatic linear or branched diol or a poly(alkyleneglycol) unit.

According to one embodiment of the invention, a product is provided inwhich the inherently radiopaque, biocompatible, bioresorbable polymercontains one or more units described by Formula II:

wherein X for each polymer unit is independently Br or I, Y is between 1and 4, inclusive, and R₄ is an alkyl, aryl or alkylaryl group with up to18 carbon atoms and from 0 to 8 heteroatoms selected from O and N.

When R₄ is an alkyl, it preferably has the structure:

wherein R₉ for each unit is independently an alkyl, aryl or alkylarylgroup containing up to 18 carbon atoms and from 0 to 8 heteroatomsselected from O and N; and R₅ and R₆ are each independently selectedfrom hydrogen and alkyl groups having up to 18 carbon atoms and from 0to 8 heteroatoms selected from O and N.

Each R₉ preferably contains a pendant COOR₁ group, wherein the subgroupR₁ is as defined previously. In one embodiment, R₉ is:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂)a, wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n, wherein a and n are independentlybetween 0 and 8 inclusive; and J₁ and J₂ are independently Br or I; andQ is selected from the group consisting of hydrogen, a free carboxylicacid group, and carboxylic acid esters and amides, wherein said estersand amides are selected from the group consisting of esters and amidesof alkyl and alkylaryl groups containing up to 18 carbon atoms andesters and amides of biologically and pharmaceutically active compounds.

More preferably, each R₉ independently has the structure:

wherein R_(5a) is defined as previously, and the COO R₁ group is asdescribed herein for; and wherein m is an integer from 1 to 8 inclusive.

In another preferred embodiment, R₉ is:

wherein j and m are independently an integer from 1 to 8, inclusive, andthe COOR₁ group is as described herein for R₉.

Preferred polymer embodiments containing R₄ aryl or alkylaryl speciesare selected so that the unit described by Formula II is a diphenol.

In another preferred embodiment of the present invention, diphenolicpolymers may comprise one or more diphenol units described by FormulaIII:

wherein X and R₂ are the same as described herein with respect toFormulas I and II, Y1 and Y2 are independently between 0 and 4,inclusive, and Y1+Y2 is between 1 and 8, inclusive.

In a more preferred version of this polymer embodiment, the diphenolicpolymer comprises one or more units described by Formula IV:

wherein each X is independently I or Br, Y1 and Y2 for each diphenolunit are independently between 0 and 4, inclusive, and Y1+Y2 for eachdiphenol unit is between 1 and 8, inclusive;

each R and R₂ are independently an alkyl, aryl or alkylaryl groupcontaining up to 18 carbon atoms and from 0 to 8 heteroatoms selectedfrom O and N, wherein R₂ further includes a pendant carboxylic acidgroup;

A is either:

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 8 heteroatoms selected from O and N; P is a poly(C₁-C₄ alkyleneglycol) unit; f is between 0 and less than 1, inclusive; g is between 0and 1, inclusive, f+g is between 0 and 1, inclusive; and the weightfraction of the poly(alkylene glycol) is about 75% or less. P ispreferably a poly(ethylene glycol) that is present in a weight fractionof about 50% or less, and more preferably about 30% or less.

R and R₂ preferably each contain a pendant COOR₁ group, wherein for R,the subgroup R₁ is independently an alkyl group ranging from 1 to about18 carbon atoms containing from 0 to 5 heteroatoms selected from O andN, and, for R₂, the subgroup R₁ is a hydrogen atom.

In one preferred embodiment, each R and R₂ independently has thestructure:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and (—CH₂-)a, wherein R₈ is selected from the group consisting of—CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)n, wherein a and n are independentlybetween 0 and 8 inclusive; and J₁ and J₂ are independently Br or I; and,for each R₂, Q comprises a free carboxylic acid group, and, for each R,Q is independently selected from the group consisting of hydrogen andcarboxylic acid esters and amides, wherein said esters and amides areselected from the group consisting of esters and amides of alkyl andalkylaryl groups containing up to 18 carbon atoms and esters and amidesof biologically and pharmaceutically active compounds.

More preferably, each R and R₂ independently has the structure:

wherein R_(5a) is defined as previously with regard to Formula II, andthe COOR₁ group is as described herein for R and R₂. In a more preferredembodiment, R and R₂ species may be selected from:

wherein j and m are independently an integer from 1 to 8, inclusive, andthe and the COOR₁ group is as described herein for R and R₂.

In another variation to the polymer, each R₁ subgroup for R is ethyl orbutyl.

In another embodiment, A is —C(═O)—.

In another embodiment, A is:

wherein R₃ is a saturated or unsaturated, substituted or unsubstitutedalkyl, aryl, or alkylaryl group containing up to about 18 carbon atomsand 0 to 8 heteroatoms selected from O and N, and more preferably C4-C12alkyl, C8-C14 aryl, or C8-C14 alkylaryl. In another preferredembodiment, R₃ may be selected from —CH2-C(═O)—, —CH2-CH2-C(═O)—,—CH═CH— and (—CH2-)z, wherein z is an integer from 0 to 8, inclusive.

Polymers according to the present invention include embodiments in whichiodine and bromine are both present as ring substituents.

According to another aspect of the preferred embodiments, anembolotherapy product is provided, formed from a ring-substitutedpolymer containing one or more units described by Formula V:

wherein each X is independently iodine or bromine; each y isindependently 1 or 2; each R₄ and R₆ are independently an alkyl, aryl oralkylaryl group containing up to 18 carbon atoms and from 0 to 8heteroatoms selected from O and N; and A, P, f and g are the same asdescribed above with respect to Formula IV.

R₄ and R₆ preferably each contain a pendant COOR₁ group, wherein for R₆,the subgroup R₁ is independently an alkyl group ranging from 1 to about18 carbon atoms containing from 0 to 5 heteroatoms selected from 0 or N,and, for R₄, the subgroup R₁ is a hydrogen atom. More preferably, eachR₄ and R₆ is:

wherein R_(5a) is defined as previously with regard to Formula II, andthe COOR₁ group is as described herein for R₄ and R₆.

It is understood that the presentation of the various polymer formulaeis schematic and that the Formulae IV and V polymer structuresrepresented are random copolymers with respect to the position of P sothat the different subunits can occur in random sequence throughout thepolymeric backbone. In most cases, A is connected to either P or aphenolic ring.

Typically, P is a poly(alkylene glycol) unit having a molecular weightof about 10,000 or less, and more typically, about 4000 or less. P ispreferably a poly(ethylene glycol) unit having a molecular weightbetween about 1000 and about 2000.

When A is a carbonyl (C═O), the Formula IV polymers of the preferredembodiments comprise polycarbonates and the Formula V polymers comprisepoly(amide carbonates).

When A is:

the Formula IV polymers of the preferred embodiments comprisepolyarylates and the Formula V polymers comprise poly(ester amides).

In embodiments wherein Formula IV defines a polyarylate and Formula Vdefines a poly(ester amide), R₃ is a saturated or unsaturated,substituted or unsubstituted alkyl, aryl, or alkylaryl group containingup to about 18 carbon atoms and from 0 to 8 heteroatoms selected from Oand N. In preferred embodiments, R₃ is an alkyl group containing betweenabout 2 and about 12 carbon atoms. In some preferred embodiments, R₃ iseither a straight or branched chain alkyl group. In more preferredembodiments, the R₃ group is —CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂— or—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—. The R₃ groups can be substituted with anysuitable functional group that, preferably, does not or tends not, tocross-react with other monomeric compounds during polymerization orotherwise interfere significantly with the formation of the presentpolymers via polymerization as described below. In cases where crossreaction can occur, one skilled in the art can utilize methods, such asuse of protecting groups or other methods known in the art, to obtain apreferred compound.

In certain preferred embodiments, R₃ is selected such that theA-moieties in Formulae IV and V are derived from dicarboxylic acids thatare naturally occurring metabolites or highly biocompatible compounds.For example, in some embodiments, R₃ is selected such that thepolyarylate A-moieties in Formula III are derived from the intermediatedicarboxylic acids of the cellular respiration pathway known as theKrebs Cycle. Such dicarboxylic acids include sebacic acid, adipic acid,oxalic acid, malonic acid, glutaric acid, pimelic acid, suberic acid andazelaic acid. Accordingly, R₃ is more preferably a moiety selected from—CH═CH— and (—CH₂-)_(z), wherein z is an integer from 0 to 8, andpreferably from 4 to 8, inclusive.

In certain embodiments, X in Formulae IV and V is preferably iodine. Incertain embodiments, when present, P in Formulae IV and V is preferablya poly(ethylene glycol) unit. In Formulae IV and V, f preferably rangesfrom greater than 0.1 to about 0.3 inclusive, and more preferably fromgreater than 0.2 to about 0.25 when present. As illustrated in FormulaeIV and V, and unless otherwise indicated, the molar fractions reportedare based on the total molar amount of dicarboxylic acid or —C(═O)—units, carboxylic acid ester monomeric units, free carb-oxylic acidunits, and poly(alkylene glycol) units in the polymeric units ofFormulae IV and V.

Applicants have recognized that the molar fraction of free carboxylicacid units, such as desaminotyrosyl tyrosine (DT) units, in the polymersof the preferred embodiments can be adjusted to likewise adjust thedegradation/resorbability of the embolotherapy compositions of thepresent invention. For example, applicants have recognized that polymerscomprising about 35% free carboxylic acid units (a molar fraction ofabout 0.35) are about 90% resorbed in about 15 days, which may beclinically desirable for embolotherapy agents. Stated another way, thehigher the molar fraction of carboxylic acid units, the shorter thelifetime of the embolotherapy agents in the body. In certain embodimentswhere lifetimes of the embolotherapy agents from several weeks toseveral months are required, polymers having a range of “g” values fromabout 0.2 to about 0.3 tend to be desirable. According to preferredembodiments, the molar fraction, g, of repeating units in Formulae IVand V derived from carboxylic acid units ranges from greater than about0.1 to about 0.3 inclusive, preferably from greater than about 0.2 toabout 0.3. However, the present invention also includes slowly-resorbingcompositions and devices prepared from polymers in which g=0.

In certain preferred embodiments for embolotherapy agents, thecopolymers employed have weight-average molecular weights (Mw) of fromabout 20,000 to about 200,000, preferably from about 50,000 to about150,000, and more preferably from about 75,000 to about 100,000. Thepolydispersity (Pa) values of the copolymers are in the range of about1.5 to about 2.5 and are usually about 2. The correspondingnumber-average molecular weights (Mn) of the copolymers forembolotherapy agents can be calculated as described above and will befrom about 10,000 to about 100,000, more preferably from about 25,000 toabout 75,000, and even more preferably from about 37,500 to about50,000. The molecular weights are measured by gel permeationchromatography (GPC) relative to polystyrene standards without furthercorrection.

Methods of Manufacture

The embolotherapy polymers of Formula IV can be prepared via any of avariety of methods. As noted above, the polymers described by Formula IVoptionally include ring-substituted diphenolic polycarbonates orpolyarylates comprising diphenolic acid ester units with pendant COOR₁groups, diphenolic units with pendant COOH groups, and poly(alkyleneglycol) units in the defined relative amounts. Accordingly, the freecarboxylic acid group polymers are prepared by methods comprisingpolymerizing a desired ratio of poly(alkylene glycol)s and one or morering-substituted diphenol monomer compounds (including an amount ofmonomer compounds with pendant COOR₁ groups for which the subgroup R₁ isa protecting group, preferably a tert-butyl ester group, in astoichiometrically quantity equivalent to the molar fraction of pendantCOOH groups desired), followed by a deprotection reaction to remove thetert-butyl ester protecting groups to form the pendant COOH groups.

The Formulae V poly(amide carbonates) and poly(ester amides) aresimilarly polymerized from a desired ratio of poly(alkylene glycol) andring-substituted aliphatic-aromatic dihydroxy acid ester units withpendant COOR₁ groups (including an amount of monomer compounds withpendant COOR₁ groups for which the subgroup R₁ is a protecting group,preferably a tert-butyl ester group, in a stoichiometrically quantityequivalent to the molar fraction of pendant —COOH groups desired), andthen deprotected.

Examples of methods adaptable for use to prepare polycarbonate orpolyarylate polymers of the preferred embodiments are disclosed in U.S.Pat. Nos. 5,099,060, 5,587,507, 5,658,995, 5,670,602, 6,120,491, and6,475,477 the disclosures of which are incorporated herein by reference.Other suitable processes, associated catalysts and solvents are known inthe art and are taught in Schnell, Chemistry and Physics ofPolycarbonates, (Interscience, New York 1964), the teachings of whichare incorporated herein by reference.

Polycarbonates can also be produced using the novel polymerizationmethod disclosed in the co-pending, commonly owned U.S. patentapplication Ser. No. 10/952,202, published as US 2006/0034769 A1 on Feb.16, 2006, the disclosure of which is incorporated in its entirety byreference. Briefly, the method comprises dissolving the diphenolmonomers and polyethylene glycol in methylene chloride containing 0.1Mpyridine or triethylamine. A solution of phosgene in toluene is thenadded at a constant rate, followed by quenching and work up of thepolymer. Residual pyridine (if used) is then removed by agitation of atetrahydrofuran (THF) polymer solution with a strongly acidic resin,such as AMBERLYST™ 15. This method can be widely applied to anypolycarbonate of Formula II.

Methods for preparing diphenol monomers for use in making the presentpolymers are disclosed, for example, in U.S. Pat. Nos. 5,587,507, and5,670,602. In particular, such references disclose the preparation ofnon-ester desaminotyrosyl-tyrosine free carboxylic acid (DT), as wellas, desaminotyrosyl-tyrosine esters, including the ethyl (DTE), butyl(DTB), hexyl (DTH), octyl (DTO), benzyl (DTBn), and other esters.Iodine- and bromine-substituted diphenol monomers can be prepared, forexample, by coupling together, via any of the procedures disclosedherein, two phenol compounds in which either or both of the phenol ringsare iodine or bromine substituted, or forming a diphenol that isiodinated or brominated after coupling via any suitable iodination orbromination method.

Methods for preparing the Formula V poly(ester amides) and poly(amidecarbonates), and the aliphatic-aromatic dihydroxy monomers from whichthey are polymerized, including ring-iodinated or brominated monomers,are described in U.S. Pat. No. 6,284,862, the disclosure of which isincorporated by reference. The disclosed poly(amide carbonate)polymerization process can be adapted to use the above-discussed processin which a toluene solution of phosgene replaces bubbling gaseousphosgene through a monomer solution.

While any of the aforementioned processes are adaptable for use herein,preparation of the polycarbonates, polyarylates, poly(ester amides) andpoly(amide carbonates) of the preferred embodiments having pendant freecarboxylic acid groups from monomers having free carboxylic acid groups(such as DT monomers) can occur with cross-reaction of the monomercarboxylic acid groups with co-monomers. Accordingly, in certainpreferred embodiments, the polymers of the preferred embodiments areprepared by polymerizing iodine or bromine ring substituted alkyl estermonomers with poly(alkylene glycols) and temporarily protected free acidmonomers (monomers wherein the free acid functionality is masked using atemporary protecting group), which may also have iodine or brominering-substituents, to form a polycarbonate, polyarylate, poly(esteramide) or poly(amide carbonate) polymeric unit from which the temporaryprotecting groups are selectively removable to produce the correspondingfree carboxylic acid groups. This method can be widely applied to anypolymer of Formula II for which a pendant free carboxylic acid group isintended.

Any of a wide variety of suitable protection/deprotection methods can beadapted for use in the preparation of the polymeric devices of thepreferred embodiments, including the methods for converting DTBnmoieties to DT moieties as described, for example, in U.S. Pat. No.6,120,491, incorporated herein by reference. A similar method by whichpoly(ester amides) and poly(amide carbonates) with free carboxylic acidgroups are prepared by the hydrogenolysis of corresponding benzyl estercopolymers is described in the aforementioned U.S. Pat. No. 6,284,862.In other words, the method of U.S. Pat. No. 6,120,491 can be extended toany polymer of Formula II for which a pendant free carboxylic acid groupis intended. In preferred embodiments, the polymers of the preferredembodiments, are produced using the novel deprotection method of thecommonly owned U.S. Patent Application No. 60/601,743 filed by JoachimB. Kohn, Durgadas Bolikal, Aaron F. Pesnell, Joan Zeltinger, Donald K.Brandom and Eric Schmid on Aug. 13, 2004 entitled “Radiopaque PolymericMedical Devices.” T-butyl ester protecting groups on hydrolyticallyunstable polymers are selectively removed to provide new polymers withfree carboxylic acid groups in place of the t-butyl ester groups.

The polymer is contacted with the acid by dissolving the polymer in asuitable solvent containing an effective amount of the acid. Anysuitable inert solvent in which the polymer to be deprotected is solublecan be used in the reaction mixture of the providing step of the presentmethod. Examples of suitable solvents include, but are not limited to,chloroform, methylene chloride, THF, dimethylformamide, and the like. Incertain preferred embodiments, the solvent comprises methylene chloride.

Any suitable weak acid capable of facilitating the selective removal ofa t-butyl protecting group from the carboxylic acid group of a providedpolymer by acidolysis can be used according to the present method.Examples of certain suitable weak acids include acids having a pK_(a) offrom about 0 to about 4, including formic acid, trifluoroacetic acid,chloroacetic acid, and the like. In certain preferred embodiments theweak acid is trifluoroacetic acid.

The amount of weak acid used should be the maximum quantity that can beadded to the solvent without interfering with polymer solubility. Theweak acid can serve as the solvent for polymers soluble therein. In thisembodiment, a preferred acid is formic acid.

The contacting step, or portions thereof, can be conducted under anysuitable conditions effective to selectively remove t-butyl protectinggroups via acidolysis. Those of skill in the art will be readily able toadapt any of the wide range of acidolysis methods for use in thecontacting step of the preferred embodiments to selectively removet-butyl groups without undue experimentation. For example, in certainpreferred embodiments, the contacting step is conducted at about 25° C.and about 1 atm.

In light of the disclosure herein, those of skill in the art will bereadily able to produce a variety of hydrolytically unstable polymerswith free carboxylic acid groups, and especially polymers of thepreferred embodiments, for instance, for use in a variety of medicaldevices, from corresponding polymers comprising t-butyl protected freecarboxylic acid repeating units.

After polymerization and deprotection, appropriate work-up of thepolymers of the preferred embodiments can be achieved by any of avariety of known methods to produce embolotherapy compositions anddevices for use in the methods of the preferred embodiments. Forexample, in certain preferred embodiments, the polymers are shaped intoparticles suitable for use in compositions for embolizing or occluding abody lumen, preferably a blood vessel. Examples of preferred particlesinclude, but are not limited to, spherical particles, geometricallynon-uniform particles, porous particles, solid particles, hollowparticles, and particles having an excluded diameter in the range ofabout 10 to about 3000 microns and more preferably in the range of about40 to 2,400 microns. In other embolotherapy products, the polymers maybe formed into hydrogels for use in embolizing or occluding a bodylumen.

Any of a variety of conventional methods for producing polymericparticles, hydrogels, and the like can be adapted for use in thepreferred embodiments. In light of the disclosure herein, those of skillin the art will be readily able to produce the embolotherapy products ofthe preferred embodiments without undue experimentation.

Polymer particles, for example, are typically prepared by adding adilute solution (about 5 wt %) of polymer in a solvent for the polymer,such as dimethyl sulfoxide (DMSO), through a narrow gauge needle to avolume of water containing an appropriate surfactant. The needle gaugeselected will determine the polymer particle size. The precipitatedpolymer spheres are isolated by filtration through a drop funnel andpermitted to air dry, followed by cryogenic grinding and drying undervacuum at an elevated temperature selected to prevent the formation ofagglomerates (about 50° C.).

One of ordinary skill in the art can adapt the polymers used in thepreferred embodiments to the known processes for producing embolotherapypolymer particles without undue experimentation. Particle size rangeswill vary depending upon the embolotherapy indication. Polymer particlesizes are typically in the range of about 10 to 3000 microns, and moretypically grouped as follows: about 45 to about 90 microns (μm), about90 to about 190 μm, about 190 to about 300 μm, about 300 to about 500μm, about 500 to about 710 μm, about 710 to about 1,000 μm, about 1,000to about 1,400 μm, about 1,400 to about 2,000 μm, about 2,000 to about2,400 μm and about 2,400 to about 3,000 μm.

The PEG-containing polymers used in the preferred embodiments have beendiscovered to have surface properties well-suited for passage through anarrow gauge needle to form micron-sized particles.

Polymer Formulations

In another preferred embodiment of the above-described products andmethods, the polymers are formulated with an effective amount of atleast one magnetic resonance enhancing agent. In yet another preferredembodiment of the above-described products and methods, the polymers areformulated with effective amounts of at least one therapeutic agent andat least one magnetic resonance enhancing agent. In yet anotherpreferred embodiment of the above-described products and methods, thepolymers are formulated with a radiopacifying agent for instance, butnot limited to iodine, bromine, barium, bismuth, gold, platinum,tantalum, tungsten, and mixtures thereof.

In preferred aspects, the inherently radiopaque, biocompatible,bioresorbable polymers may be made in the form of spherical particles.In the alternative, the polymers may be made in the form ofgeometrically non-uniform particles. Either spherical or geometricallynon-uniform particles may be hydrogel in character wherein the particlesare porous, solid or hollow. The particles may have an excluded diameterin the range of about 10 to about 5000 microns, preferably about 40 to3000 microns and more preferably about 45 to 2,400 microns. Theparticles may incorporate one or more of the above-disclosed therapeuticagents, magnetic resonance enhancing agents and radiopacifying agents.

Examples of preferred magnetic resonance enhancing agents include, butare not limited to, gadolinium salts such as gadolinium carbonate,gadolinium oxide, gadolinium chloride, mixtures thereof, and the like.In compositions and devices containing a magnetic resonance enhancingagent, an amount of magnetic resonance enhancing agent sufficient forradiologic imaging is used, which can again be determined by one ofordinary skill in the art without undue experimentation.

In certain embodiments, the embolotherapy compositions and devices ofthe preferred embodiments further comprise radio-opacifying agents. Incertain embodiments, embolotherapy compositions and devices alsocomprise compositions and devices formed from non-iodinated andnon-brominated analogs of the Formula II polymers to which aradio-opacifying agent has been added. Preferred embodiments can includeFormula II polymers as such compound analogs. Radio-opacifying agentscan be added to the Formula II polymers to enhance their radio-opacity.Examples of preferred radio-opacifying agents include, but are notlimited to, iodine metal, organic iodine compounds, bromine, bariumsulfate, bismuth oxide, gold, platinum, tantalum, tungsten, mixturesthereof, and the like.

Embolotherapy Methods

According to another aspect of the preferred embodiments, methods aredisclosed for embolizing a body lumen by introducing into the body lumenan effective amount of an embolotherapy product prepared from theinherently radiopaque, biocompatible, bioresorbable polymers disclosedherein.

In another preferred embodiment of the above-described products, aresorbing inherently radiopaque composition of biocompatible embolicparticles may be formulated for the specific treatment and re-treatmentof cancerous tumors. A resorbing formula will allow for the multiplechemotherapeutic treatments. Moreover, the flexible chemistry of thepreferred embolotherapy products allows tuning of the resorptionprofile, such that residence time within the vessels can be readilymodified by changing the polymer structure—as detailed below. Forexample, embolic particles of the present invention, chemicallyformulated to resorb could be implanted in conjunction with achemotherapeutic agent in order to restrict application of thechemotherapeutic agent to the cancerous tissue. Such a concentratedattack on the cancer cells would be particularly desired for example inthe case of hepatic carcinoma. The chemotherapeutic agent could be onthe particles, in the particles and/or bonded to the particle polymerand/or introduced with the polymer as in a delivery solution. In thisfashion the agent may have its therapeutic effect. Upon resorption ofthe embolic agent and recanalization of the vessels, the process couldthen be repeated. The inherently radiopaque particles allows morecontrolled delivery not only of the particles but also the therapeutic,and allows for multiple treatment approach, which is not currentlypossible and represents a significant unmet therapeutic need.

Thus, according to another aspect of the preferred embodiments, methodsare disclosed for enhancing the local delivery of a therapeutic agent toa tissue by (1) administering to a blood vessel associated with thetissue an amount of an embolotherapy product prepared from theinherently radiopaque, biocompatible, bioresorbable polymers disclosedherein sufficient to reduce the blood flow from the tissue; (2)administering the therapeutic agent to the blood vessel separately or incombination with the embolotherapy product, so that the local deliveryof the therapeutic agent is enhanced; and (3) repeating the steps ofadministering the embolotherapy product and therapeutic agent after theembolotherapy product first administered has degraded sufficiently toallow for re-access to said blood vessel.

In accordance with another preferred embodiment of the presentinvention, a method is disclosed for embolizing a body lumen. The methodcomprises introducing into the body lumen an effective amount of acomposition, comprising a biocompatible, bioresorbable polymer, whereinthe polymer comprises a radiopaque moiety selected from the groupconsisting of iodine, bromine, barium, bismuth, gold, platinum,tantalum, tungsten and mixtures thereof. More preferably, the methodcomprises the step of introducing into a blood vessel an embolotherapyparticle comprising a biocompatible, bioresorbable polymer comprisingsufficient halogen atoms to render the particle radiopaque.

In certain embodiments these bioresorbable, inherently radiopaqueembolic agents may be delivered by the conventional delivery system suchas a guide catheter when embolizing tumors, vascular malformations(e.g., for uterine fibroids, tumors (i.e., chemo-embolization),hemorrhage (e.g., during trauma with bleeding) and arteriovenousmalformations, fistulas and aneurysms. In another embodiment thesebioresorbable, inherently radiopaque embolic agents may be delivered byless conventional delivery systems, for example, direct injection into abody lumen via a syringe or other non-catheter system to providecosmetic treatment for spider veins and/or varicose veins. Indeed, wheredirect injection into surface veins is undertaken, the polymericembolotherapy product may not need to be radiopaque. Accordingly, forapplications such as cosmetic treatment for spider veins and/or varicoseveins, non-halogenated polymers in accordance with certain embodimentsof the present invention may be used with efficacy. The addition and/orpolymer-based delivery of therapeutic agents may also be advantageouslyused for such cosmetic clinical indications.

The preferred embodiments further provide methods for embolizing a bodylumen comprising introducing into the body lumen an embolizingcomposition prepared from a polymer of Formula II. According to certainpreferred embodiments, effective amounts of compositions are employedcontaining one or more of the following: spherical particles,geometrically non-uniform particles, porous particles, solid particles,hollow particles, particles having an excluded diameter in the range ofabout 10 to about 3000 microns and more preferably from about 40 toabout 2,400 microns, hydrogels, and any combinations thereof. Anysuitable conventional methods for introducing an embolotherapycomposition to a body lumen for embolizing the body lumen can be adaptedfor use in the preferred embodiments. For example, traditional methodsfor introducing PVA embolics to a body lumen can be used withsubstituting the compositions of the preferred embodiments for the PVAembolics.

Therapeutic Agents

According to a preferred embodiment of the above-described embolotherapyproducts and methods, the polymers may be formulated with an effectiveamount of at least one therapeutic agent (e.g., a pharmaceutical agentand/or biologic agent) sufficient to exert a selected therapeuticeffect. The term “pharmaceutical agent”, as used herein, encompasses asubstance intended for mitigation, treatment, or prevention of diseasethat stimulates a specific physiologic (metabolic) response. The term“biologic agent”, as used herein, encompasses any substance thatpossesses structural and/or functional activity in a biological system,including without limitation, organ, tissue or cell based derivatives,cells, viruses, vectors, nucleic acids (animal, plant, microbial, andviral) that are natural and recombinant and synthetic in origin and ofany sequence and size, antibodies, polynucleotides, oligonucleotides,cDNA's, oncogenes, proteins, peptides, amino acids, lipoproteins,glycoproteins, lipids, carbohydrates, polysaccharides, lipids,liposomes, or other cellular components or organelles for instancereceptors and ligands. Further the term “biological agent”, as usedherein, includes virus, serum, toxin, antitoxin, vaccine, blood, bloodcomponent or derivative, allergenic product, or analogous product, orarsphenamine or its derivatives (or any trivalent organic arseniccompound) applicable to the prevention, treatment, or cure of diseasesor injuries of man (per Section 351(a) of the Public Health Service Act(42 U.S.C. 262(a)). Further the term “biologic agent” may include 1)“biomolecule”, as used herein, encompassing a biologically activepeptide, protein, carbohydrate, vitamin, lipid, or nucleic acid producedby and purified from naturally occurring or recombinant organisms,antibodies, tissues or cell lines or synthetic analogs of suchmolecules; 2) “genetic material” as used herein, encompassing nucleicacid (either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA),genetic element, gene, factor, allele, operon, structural gene,regulator gene, operator gene, gene complement, genome, genetic code,codon, anticodon, messenger RNA (mRNA), transfer RNA (tRNA), ribosomalextrachromosomal genetic element, plasmagene, plasmid, transposon, genemutation, gene sequence, exon, intron, and, 3) “processed biologics”, asused herein, such as cells, tissues or organs that have undergonemanipulation. The therapeutic agent may also include vitamin or mineralsubstances or other natural elements.

The amount of the therapeutic agent is preferably sufficient to performas, but not limited to, a chemotherapeutic agent, non-steroidalanti-inflammatory agent, and/or steroidal anti-inflammatory agent topromote a desirable biological and/or physiological response or toaffect some other state of the embolized tissue, for instance, attracthealing cells or those that produce extracellular matrix to aid healingof the embolized body lumen.

Therapeutic agents can be incorporated onto the embolotherapy product onat least one region of the surface, or in some cases in the product,thereby providing local release of such agents. In some preferredembodiments, the therapeutic agent is delivered from a thin polymercoating or other carrier on the particle surface. In another preferredvariation, the therapeutic agent is delivered by means of a polymercoating. In other preferred embodiments of the embolotherapy product,the therapeutic agent is delivered from at least one region or onesurface of the embolotherapy product. In other preferred embodiments ofthe embolotherapy product, the therapeutic agent is contained within theembolotherapy product as the agent is blended with the polymer oradmixed by other means known to those skilled in the art. In otherpreferred embodiments, the therapeutic agent can be chemically bonded toa polymer or other carrier used to coat the particles and/or bonded toat least one portion of the particle polymer and/or bonded to theparticle polymer indirectly by means of a separate linker or ligand. Inanother variation, the embolotherapy product may comprise more than onetherapeutic agent, for example, coated on at least a portion of theparticle surface, admixed within the polymeric matrix, etc.

In another preferred embodiment of the above-described products andmethods, the embolotherapy product may be formulated with an effectiveamount of a coating that is a biocompatible, bioresorbable coatingsufficient to promote a desirable biological and/or physiologicaleffect.

In certain embodiments, the embolotherapy compositions and devices ofthe preferred embodiments further comprise therapeutic agents (e.g., apharmaceutical agent and/or biologic agent) as previously defined hereinand/or magnetic resonance enhancing agents. The amount of thetherapeutic agent is preferably sufficient to perform as, but notlimited to, a chemotherapeutic agent, non-steroidal anti-inflammatoryagent, and/or steroidal anti-inflammatory agent to promote a desirablebiological and/or physiological response or to affect some other stateof the embolized tissue, for instance, attract healing cells or thosethat produce extracellular matrix to aid healing.

Therapeutic agents can be incorporated onto the embolotherapy product onat least one region of the surface, or in some cases in the product,thereby providing local release of such agents. In some preferredembodiments, the therapeutic agent is delivered from a thin polymercoating on the polymeric particle surface. In another preferredvariation, the therapeutic agent is delivered by means of no polymercoating. In other preferred embodiments of the embolotherapy product,the therapeutic agent is delivered from at least one region or onesurface of the embolotherapy product. In other preferred embodiments ofthe embolotherapy product, the therapeutic agent is contained within theembolotherapy product as the agent is blended with the polymer oradmixed by other means known to those skilled in the art.

The therapeutic agents in accordance with preferred aspects of theinvention may be classified in terms of their sites of action in thehost, for example they may exert their actions extracellularly or atspecific membrane receptor sites, at the plasma membrane, within thecytoplasm, and in the nucleus. Therapeutic agents may be polar orpossess a net negative or positive or neutral charge; they may behydrophobic, hydrophilic or zwitterionic or have a great affinity forwater. Release may occur by controlled release mechanisms, diffusion,interaction with another agent(s) delivered by intravenous injection,aerosolization, or orally. Release may also occur by application of amagnetic field, an electrical field, or use of ultrasound.

Examples of suitable therapeutic agents include, but are not limited to,chemotherapeutic agents, non-steroidal anti-inflammatory agents,steroidal anti-inflammatory agents. Examples of preferredchemotherapeutic agents include, but are not limited to, taxanes,taxinines, taxols, paclitaxel, dioxorubicin, cis-platin, adriamycin,bleomycin, and the like. Examples of preferred non-steroidalanti-inflammatory compounds include, but are not limited to, aspirin,dexamethasone, ibuprofen, naproxen, Cox-2 inhibitors, such asRofexcoxib, Celecoxib and Valdecoxib, and the like. Examples ofpreferred steroidal anti-inflammatory compounds include, but are notlimited to, dexamethasone, beclomethasone, hydrocortisone, prednisone,and the like.

Any suitable amount of one or more therapeutic agents may be used.Preferably, an amount of therapeutic agent effective to have a localtherapeutic effect is employed, which can be readily determined by oneof ordinary skill in the art without undue experimentation.

Embolotherapy Products Having Surface Coatings

In addition to embolotherapy products that may deliver a therapeuticagent, for instance delivery of a biological polymer on the product suchas thrombogenic collagen or fibronectin or a repellantphosphorylcholine, the embolotherapy products may be delivered or coatedwith bioresorbable polymers predetermined to promote biologicalresponses in the embolized body lumen desired for certain clinicaleffectiveness. Further the coating may be used to mask the surfaceproperties of the polymer used to comprise the embolotherapy particles.The coating may be selected from the broad class of any non-halogenatedor halogenated biocompatible bioresorbable polymer which may or may notcomprise any poly(alkylene glycol). These polymers may includecompositional variations including homopolymers and heteropolymers,stereoisomers and/or a blend of such polymers. These polymers mayinclude for example, but are not limited to, polycarbonates,polyarylates, poly(ester amides), poly(amide carbonates), trimethylenecarbonates, polycaprolactones, polydioxanes, polyhydroxybutyrates,polyhydroxy-valerates, polyglycolides, polylactides and stereoisomersand copolymers thereof, such as glycolide/lactide copolymers. In apreferred embodiment, the embolotherapy product is coated with a polymerthat exhibits a high absorptive affinity for fibrinogen or plasmaproteins to promote clot formation, for instance in the case ofhemorrhage. For instance poly(DTE carbonate) and poly(I2DTE carbonate)promote high levels of fibrinogen adsorption; further a coating maycomprise a polymer with a positive charge that attracts the negativecharge of red blood cells' outer membranes thereby inducing a the body'snormal clotting processes. In another preferred embodiment, theembolotherapy product is coated with a polymer that exhibits an affinityfor cells, (e.g., mesenchymal, fibroblast, stromal cells andparenchymal) to promote healing and tissue resorption and remodeling ofthe embolized tissue, for instance in the case of treating uterinefibroids. In yet another preferred embodiment, the embolotherapy productis coated with a polymer that repels the attachment and/or proliferationof specific cells, for instance endothelial cells of microvessels knownto vascularize a tumor; in this instance the polymer coating on theembolic product may slow down or inhibit further vascularization of anembolized tumor. In another preferred embodiment, the embolotherapyproduct is coated with a polymer that attracts cells and/or promotestheir proliferation and/or deposition of extracellular matrix moleculesthat support formation of a reparative tissue (e.g., granulationtissue). This may include attraction of inflammatory cells such asmacrophages that lead to successful healing and/or formation offibroconnective tissue. In a preferred embodiment, the embolotherapyproduct is coated with a polymer that promotes tissue deposition as inthe case of arteriovenous malformations and aneurysms.

The following non-limiting examples set forth below illustrate certainaspects of the invention. These examples are not intended to limit thescope, but rather to exemplify preferred embodiments. All parts andpercentages are by weight unless otherwise noted and all temperaturesare in degrees Celsius.

EXAMPLES Nomenclature and Abbreviations Used

The following abbreviations are used to identify the various iodinatedcompounds. TE stands for tyrosine ethyl ester, DAT stands fordesaminotyrosine and DTE for desaminotyrosyl tyrosine ethyl ester. Thepolymer obtained by phosgenation of DTE is denoted as poly(DTEcarbonate). An “I” before the abbreviation shows mono-iodination (e.g.ITE stands for mono-iodinated TE) and an I₂ before the abbreviationshows di-iodination (e.g. I₂DAT stands for di-iodinated DAT). In DTE, ifthe “I” is before D, it means the iodine is on DAT and if “I” is afterD, it means the iodine is on the tyrosine ring (e.g. DI₂TE stands forDTE with 2 iodine atoms on the tyrosine ring). The following diagramillustrates this nomenclature further.

Resorption Testing

Polymer degradation rate was measured in vivo and in vitro using thematerials and methods described in Abramson st al., “Small changes inpolymer structure can dramatically increase degradation rates: theeffect of free carboxylate groups on the properties of tyrosine-derivedpolycarbonates,” Sixth World Biomaterials Congress Transactions, Societyfor Biomaterials 26th Annual Meeting, Abstract 1164 (2000), thedisclosure of which is

incorporated by reference.

Example 1: Preparation of Poly(60%I₂DTE-co-20%I₂DT-co-20%PEG2KCarbonate)

Into a three necked round-bottomed flask, equipped with a mechanicalstirrer, a thermometer, a reflux condenser and a rubber septum wereadded 18.3 g (0.03 mol) of I₂DTE, 6.38 g (0.01 mol) of I2DTtBu, 20 g(0.01 mol) of PEG2000, and 300 ml of methylene chloride. On stirring aclear light yellow solution was obtained. To this was added 15.1 ml(0.15 mol) of pyridine. In a gas tight plastic syringe was placed 30 mlof a 20% solution of phosgene in toluene (0.0576 mol), which was addedto the reaction flask over 3 h using a syringe pump. The molecularweight was determined by analyzing an aliquot of the reaction mixture byGPC. Additional phosgene solution (up to 10%) was needed to achievedesired molecular weight. The reaction mixture was quenched with 110 mlof THF and 10 ml of water. The polymer was precipitated by adding thereaction mixture to 1.5 L of cold 2-propanol in high speed Waringblender.

The resulting gluey polymer was ground with two portions of 0.5 L2-propanol. The fine granular polymer particles were isolated byfiltration and dried in a vacuum oven. To remove the t-Butyl protectinggroup, the polymer was dissolved in trifluoroacetic acid to obtain a 20%solution. After stirring the solution at room temperature for 4 h, thepolymer was precipitated by adding to 2-propanol and then furthergrinding with 2-propanol to remove the excess TFA. The product wasisolated by filtration, washed with IPA and dried in vacuum oven.

Those skilled in the art will recognize that radiopaquebromine-substituted polymers can be similarly prepared by replacingiodine with bromine in the starting materials.

Example 2: Preparation of Poly(I2DTE-co-2.5Mole%PEG2K Carbonate)

A polymer containing 97.5% mole percent I₂DTE and 2.5% poly(ethyleneglycol) of molecular weight 2000 (poly(97.5%I₂DTE-co-2.5%PEG2Kcarbonate)) was prepared as follows. Into a three necked round-bottomedflask, equipped with a mechanical stirrer, a thermometer, a refluxcondenser and a rubber septum, were added 29.7 g (0.0488 mol) of I₂DTE,2.5 g (0.00125 mol) of PEG2000, and 215 ml of methylene chloride. Onstirring a clear light yellow solution was obtained. To this was added15.1 ml (0.15 mol) of pyridine. In a gas tight plastic syringe wasplaced 30 ml of a 20% solution of phosgene in toluene (0.0576 mol),which was added to the reaction flask over 3 h using a syringe pump. Themolecular weight was determined by analyzing an aliquot of the reactionmixture by GPC. Additional phosgene solution (up to 10%) was added toachieve the desired molecular weight. The reaction mixture was quenchedwith 110 ml of tetrahydrofuran and 10 ml of water. The polymer wasprecipitated by adding the reaction mixture to 1.5 L of cold 2-propanolin high speed Waring blender. The resulting polymer was ground with twoportions of 0.5 L 2-propanol. The fine granular polymer particles wereisolated by filtration and dried in a vacuum oven.

Example 3: Formation of Embolotherapy Particles

A 5% w/w DMSO solution of the polymer of Example 2 was prepared bydissolving 0.650 g polymer in 12.35 g DMSO. A precipitation solution wasprepared by adding 3 ml of a 10 vol % aqueous solution (fromconcentrate) of ALCONOX surfactant to 300 ml water. The precipitationsolution was placed in a 600 ml container and stirred on a slow setting(<100 RPM). Adding the DMSO polymer solution to the precipitationsolution in a drop-wise fashion from a syringe through a 26-gauge needleallows for polymer spheres to precipitate. The 26-gauge needle wasground to a point to buff off the silicone coating. This reduces surfacetension, resulting in smaller drops of polymer when dispensed.

The precipitated polymer spheres were isolated through a filtered dropfunnel and allowed to air dry. The spheres were then cryogenicallyground in a coffee grinder at about 20,000 RPM with added CO₂. Theground particles were then dried overnight in a vacuum oven at 50° C.under dynamic vacuum. The dried spheres were then manually sieved intothe following particle ranges:

-   -   90-180 micron diameter    -   180-300 micron diameter    -   300-500 micron diameter    -   500-710 micron diameter

Example 4: In Vivo Evaluation or Particle Radio-Opacity

The acute radio-opacity of the embolotherapy particles of Example 3 wasevaluated by injection into the renal arterial beds of a pig. Theparticles were injected via a catheter inserted into distal renalarterial beds.

Access to the renal arterial beds was achieved with a 5F catheter over a0.035″ wire. A small profile catheter was advanced into the distalvascular bed to provide a more sub-selective injection. A baselineangiogram was taken on cine. The embolotherapy particles were mixed withsaline in a beaker at about 5 cc per 300 mg of particles and aspiratedinto 3 cc syringe. The filled 3 cc syringe and a 1 cc empty syringe wereattached to a 3-way stopcock. Settling of the particles was prevented byshuttling the suspension back forth between the two syringes.

The stopcock assembly was attached to the placed 5-Fr (0.038″ ID)multipurpose catheter. The syringe contents were injected with quickstrong injections. The loading and injection procedure was repeateduntil blood flow ceased in the target areas. Blood flow cessation wasconfirmed by injecting contrast agent.

The syringe contents contained the following particle masses*:

 90-180 um: 110 mg 180-300 um: 221 mg 300-500 um: 233 mg* 500-710 um:122 mg* *an undetermined amount of each of these size ranges did not getinjected because of catheter clogging.

The particles were visible en masse under fluoroscopy during theinjections in the absence of added contrast agent. They appeared on thefluoroscopy viewing screen like short bursts of white against a blackbackground, similar to the way contrast agents would appear, although nocontrast agent was present in the injection solution. Follow-upinjection with contrast agent revealed effective embolization of thevascular beds.

The kidneys were explanted and x-rayed ex vivo (FIGS. 1A and 1B). InFIG. 1A, a large branch of the renal artery, about fourth order,(approximately two to three millimeters in diameter) is visibly packedwith the embolotherapy material (arrow). The same artery packed withcommercially available polymer spheres would not be visible on x-ray. InFIG. 1B, a small renal artery (arrow) is also visibly packed with100-300 micron particles.

The figures demonstrate that the inherently radiopaque particles of thepreferred embodiments produce a visible cast on x-ray that isessentially homogeneously distributed in the different branches of therenal arteries. Embolization procedures are relatively risky andnear-prefect control of particle delivery is necessary. Particlesvisible on x-ray are more controllable than non-visible particles,because their deployment can be monitored in real time for a moreaccurate determination of the end point of delivery. The instantaneousfeedback on particle distribution also permits calibration of theparticle size distribution to permit more accurate delivery. Theparticles of the preferred embodiments also permit monitoring of theembolized tissue and subsequent polymer resorption by x-ray, replacingthe biopsy techniques and indirect evaluation procedures presentlyemployed.

The foregoing demonstrates that the polymers of the preferredembodiments have great promise as inherently radiopaque, non-permanentbiocompatible embolotherapy agents. Though less than standard amountswere used, effective embolization was realized with dynamic fluoroscopicvisualization and subsequently clear x-ray identification of inherentlyradiopaque particle masses in the vascular bed. It should be noted,because the contrast agent was injected only pre- and post-embolization,the radio-opacity of the particles can be the result of the inherentcharacter of the polymer.

Example 5: In-Vitro Drug Elution Kinetics

This is determined for the release of drug out of certain polymers,based on physiochemical characteristics and solvent extractionrequirements at 37° C. under “sink” conditions, and with agitation toensure dissolution homogeneity. The therapeutic substance (e.g., drug)in a polymer (see table below) may be coated on to the surface of apolymer film surfaces and it may be embedded or blended with the polymerprior to pressing the film which, emulates a embolotherapy product inthese tests.

Film size is adjusted to accommodate drug load and detection limits forquantitation. A typical procedure might include compound extraction orprecipitation, followed by quantitation using high performance liquidchromatography (HPLC). An appropriate dissolution media such as 3%Bovine Serum Albumin (BSA) or 35% Tween 20 in a phosphate buffer saline(PBS) is used. Dissolution may be determined from 24 hours out to 28days. After dissolution, the drug content of films and/or media isanalyzed. Dissolution rate is calculated for each drug using a massbalance determination from this HPLC assay. The percent dissolved iscalculated by using the quantities measured at each time point for theoverall dissolution profile.

TABLE 2 Summary of Testing of Tyrosine-Derived Polycarbonate CoatingsPoly (100% DTE) Carbonate Poly (90% DTE-co-10% DT)Carbonate¹ Poly (76%DTE-co-24% DT)Carbonate² Poly (67% DTE-co-33% DT)Carbonate Poly (95%DTE-co-5% PEG 1K) Carbonate Poly (97.5% I₂DTE-co-2.5% PEG 2K) CarbonatePoly (77.5% I₂DTE-co-20% I₂DT-2.5% PEG 2K) Carbonate Poly (67.5%I₂DTE-co-30% I₂DT-2.5% PEG 2K) Carbonate Poly (70% I₂DTE-co-20% I₂DT-10%PEG 2K) Carbonate Poly (80% I₂DTE-co-20% PEG 2K) Carbonate ¹Drug elutionwas tested in coated films as well as films with the drug embedded.²Drug elution was tested only in films with the drug embedded.

Drug elution with the various polymers (TABLE 2) that were coated onto asurface or embedded in the polymer and compressed into a film hasdemonstrated drug elution. FIG. 2 shows that elution of chemotherapeuticagent out of poly-DTE-carbonates. Other biocompatible bioresorbablepolymers may be used for this purpose. In the example of thepolycarbonates, drug elution can be tailored by modifying the polymerwith iodines on the DAT ring or by adding PEG to the back bone of thepolymer.

Example 6: Preparation of Poly(I₂DTE-co-2.5Mole%PEG_(2k) Adipate)

The diphenol I₂DTE (2.97 g, 4.87 mmol), PEG2000 (0.250 g, 0.125 mmol)and adipic acid (0.731 g, 5.04 mmol) and 0.4 g of DPTS(dimethylamonopyridyl-paratoluene sulfonate, catalyst) were weighed intoa 100 ml brown bottle with Teflon-lined cap. To the bottle is also added40 ml of methylene chloride, and securely capped. The bottle is agitatedfor 10-15 min and then 2.5 ml (2.02 g, 16 mmol) ofdiisopropylcarbodiiimide is added and continued to agitate for 2 h. Analiquot of the sample is withdrawn and after proper treatment analyzedby GPC. A Mw of about 100,000 is desirable. Once the desired Mw isreached, 200 ml of 2-propanol is added to the reaction mixture withstirring. The precipitate is collected and dried in a stream ofnitrogen. The precipitate is then dissolved in 20 ml of methylenechloride and precipitated with 200 ml of methanol. Then the polymer isdried under nitrogen, followed by drying in a vacuum oven.

Example 7: Polymerization of Poly(60%I₂DTE-co-20%I₂DT-co-20%PEG_(2k)Adipate)

The diolic components (1.83 g, 3.00 mmol of I₂DTE, 0.638 g, 1.00 mmolI₂DTtB, and 2.000 g 1.00 mmol of PEG2000), and the diacid (0.731 g, 5mmol adipic acid) and 0.4 g, of DPTS were weighed into a 100 ml brownbottle with Teflon-lined cap. To the bottle is also added 40 ml ofmethylene chloride, and securely capped. The bottle is agitated for10-15 min and then 2.5 ml (2.02 g, 16 mmol) of diisopropylcarbodiiimideis added and continued to agitate for 2 h. An aliquot of the sample iswithdrawn and after proper treatment analyzed by GPC. A Mw of about100,000 is desirable. Once the desired Mw is reached, 200 ml of2-propanol is added to the reaction mixture, with stirring. Theprecipitate is collected and dried in a stream of nitrogen. Theprecipitate is then dissolved in 20 ml of methylene chloride andprecipitated with 200 ml of methanol. Then the polymer is dried undernitrogen, followed by drying in a vacuum oven.

Deprotection:

The resulting polymer is dissolved in trifluoroacetic acid (10% w/v) andallowed to stir overnight. The following day, the polymer isprecipitated in isopropanol using a blender for mixing. The polymer isthen ground twice with fresh isopropanol, filtering with a frittedfilter between washes. Then the polymer is dried under nitrogen,followed by drying in a vacuum oven.

Example 8: Preparation of Poly(I₂DTE-co-2.5Mole%PEG_(2k) Sebacate)

The diphenol I₂DTE (2.98 g, 4.89 mmol), PEG2000 (0.250 g, 0.125 mmol)and sebacic acid (1.01 g, 5.00 mmol) and 0.4 g of DPTS are weighed intoa 100 ml brown bottle with Teflon-lined cap. To the bottle is also added40 ml of methylene chloride, and securely capped. The bottle is agitatedfor 10-15 min and then 2.5 ml (2.02 g, 16 mmol) ofdiisopropylcarbodiiimide is added and continued to agitate for 2 h. Analiquot of the sample is withdrawn and after proper treatment analyzedby GPC. A Mw of about 100,000 is desirable. Once the desired Mw isreached, 200 ml of 2-propanol is added to the reaction mixture, withstirring. The precipitate is collected and dried in a stream ofnitrogen. The precipitate is then dissolved in 20 ml of methylenechloride and precipitated with 200 ml of methanol. Then the polymer isdried under nitrogen, followed by drying in a vacuum oven.

Example 9: Preparation of Tri-Iodinated-DTE (I₂DITE)

Tri-Iodinated monomer (I₂DITE) was prepared using procedures similar tothose published in the literature by substituting I₂DAT in the place ofDAT and ITE in the place of TE. In a typical procedure 85.8 g (0.255mol) of 3-iodotyrosine ethyl ester (ITE), 104 g (0.250 mol) of I₂DAT and3 g (0.025 mol) 1-hydroxybenzotriazole were stirred with 500 ml oftetrahydrofuran in a 1 liter round-bottomed flask. The flask was cooledin an ice-water bath to 10-18° C. and 50 g (0.255 mol) of EDCI was addedand stirred for 1 h at 15-22° C. This was followed by stirring of thereaction mixture at ambient temperature for 5 h. The reaction mixturewas concentrated to 250 ml and then stirred with 1 L of water and 1 L ofethyl acetate. The lower aqueous layer was separated and discarded usinga separatory funnel. The organic layer was sequentially washed with 500ml each of 0.4 M HCl, 5% sodium bicarbonate solution and 20% sodiumchloride solution. After drying over anhydrous sodium sulfate, theorganic layer was concentrated to syrup and triturated by stirring withhexane. An off white solid is obtained. The product is characterized byHPLC and ¹H NMR.

Example 10: Preparation of Tetraiodinated DTE (I₂DI₂TE)

DTE (16.4 g, 0.046 mol) was dissolved in 300 ml of 95% ethanol. To thesolution with stirring was added 46 g (0.19 mol) of PyICl. The solutionwas stirred for 2 h when the solid slowly dissolved to give a lightyellow solution. This was added over 30 min, with stirring, to 1 literof water containing 10 g sodium thiosulfate. An off-white solidseparated and was isolated by filtration and washed with severalportions of deionized water.

The wet cake (ca 150 g) was heated with 1.5 L of ethanol until itdissolved and then allowed to cool to room temperature. The whitecrystalline solid formed was isolated by filtration and washed with 95%ethanol and dried. 32 g (81%) of the dry product was obtained. Theproduct was characterized by HPLC and ¹H NMR.

Example 11: Tri-Iodinated Polymer Containing Poly(Ethylene Glycol)

A polymer containing 80% mole percent I₂DITE and 20% poly(ethyleneglycol) of molecular weight 2000 (poly(80%I₂DITE-co-20%PEG2K carbonate))was prepared as follows. Into a three necked round-bottomed flask,equipped with a mechanical stirrer, a thermometer, a reflux condenserand a rubber septum were added 6.0 g (8.1 mmol) of I₂DITE and 4.1 g(2.05 mmol) of PEG2000, and 66 ml of methylene chloride and 3.1 ml (39mmol) of pyridine. On stirring a clear almost colorless solution wasobtained. In a gas tight plastic syringe was placed 6.5 ml of a 20%solution of phosgene in toluene (12.5 mmol), which was then added to thereaction flask over 3 h using a syringe pump. The molecular weight wasdetermined by analyzing an aliquot of the reaction mixture by GPC. Apolystyrene equivalent Mw of 200,000 was obtained. The reaction mixturewas quenched with 55 ml of tetrahydrofuran and 5 ml of water. Thepolymer was precipitated by adding the reaction mixture to 1 L of cold2-propanol in a high speed Waring blender. The resulting gluey polymerwas ground with two portions of 0.5 L 2-propanol. The fine granularpolymer particles were isolated by filtration and dried in a vacuumoven.

Example 12: Tetra-Iodinated Polymer Containing Poly(Ethylene Glycol)

A polymer containing 80% mole percent I₂DI₂TE and 20% poly(ethyleneglycol) of molecular weight 2000 (poly(80%I₂DI₂TE-co-20%PEG2Kcarbonate)) was prepared as follows. Into a three necked round-bottomedflask, equipped with a mechanical stirrer, a thermometer, a refluxcondenser and a rubber septum were added 1.55 g (1.80 mmol) of I₂DI₂TEand 0.9 g (0.45 mmol) of PEG2000, and 20 ml of methylene chloride and0.68 ml (8.6 mmol) of pyridine. On stirring a clear almost colorlesssolution was obtained. In a gas tight plastic syringe was placed 1.4 mlof a 20% solution of phosgene in toluene (2.7 mmol), which was thenadded to the reaction flask over 3 h using a syringe pump. The molecularweight was determined by analyzing an aliquot of the reaction mixture byGPC. A polystyrene equivalent Mw of 25,000 was obtained. The reactionmixture was quenched with 18 ml of tetrahydrofuran and 2 ml of water.The polymer was precipitated by adding the reaction mixture to 200 ml ofcold 2-propanol in a beaker using a magnetic stirrer. The resultinggluey polymer was ground with 200 ml of 2-propanol. The polymer obtainedwas still gluey probably due to the low molecular weight and highpoly(ethylene glycol) content.

FIG. 3a-b show X-ray comparisons of radiopaque bioresorbabledi-iodinated and tri-iodinated tyrosine-derived polycarbonate films. Thepoly(I2DITE-co-20%PEG2k) carbonate 114 micron films have a photo-densityequivalent to human bone. That of poly(80%I2DTE-co-20%PEG2k) carbonatehas a lower photo-density.

Example 13: Fibrinogen Adsorption to Polymeric Surfaces

The time course of human fibrinogen adsorption to the test polymersurfaces were measured using a Quartz Crystal Microbalance withDissipation monitoring (QCM-D, Q-Sense AB, model D300, Goeteborg,Sweden).

QCM-D is a gravimetric technique and useful for measuring in real-timethe mass of material in liquid adhering to a surface. An increase inmass bound to the quartz surface causes the crystal's oscillationfrequency to decrease. Moreover, this device can measure the change ofdissipation induced by the surface-adsorbed mass.

Quartz crystals (Q-Sense, Cat # QSX-301) were spin-coated with polymersolutions (1% polymer in methylene chloride). Commercially availablequartz crystals coated with a thin layer of stainless steel (Q-Sense,Cat # QSX-304) were included for comparison. To start a typicalexperiment, the crystals were inserted into the QCM-D instrument andincubated in phosphate-buffered saline (PBS) at 37° C. After reaching astable baseline, the fibrinogen solution was injected and the frequencyand dissipation shifts induced by adsorbed mass, were recorded inreal-time. The fibrinogen solution was incubated until the bindingsaturation was reached (as indicated by absence of further significantchanges in frequency and dissipation values). PBS without fibrinogen wasused for all rinsing steps to remove non-bound fibrinogen from thesensor surface after the adsorption process. Human fibrinogen waspurchased from Calbiochem (Cat #341576) and diluted in PBS to a finalconcentration of 3 mg/ml. All experiments were performed in triplicatewith a standard deviation of less than 12% (standard error mean).

The quartz crystals could be reused up to 10 times by applying thefollowing cleaning procedure: Quartz crystals were treated with acleaning solution (80° C., 15 min) consisting of H₂O₂ (30%), NH₄OH andultrapure water in a 1:1:5 ratio. Thereafter, crystals were extensivelyrinsed with ultrapure water and blow dried with nitrogen. Finally, thecrystals were exposed to UV and ozone for 15 min (UVO cleaner, JelightCompany, Irvine, Calif., USA).

TABLE 3 summarizes the comparative evaluation of different stent polymerformulations with respect to fibrinogen adsorption in vitro. Fibrinogenis a key blood protein. The degree of fibrinogen adsorption on anartificial surface in contact with blood is widely regarded as areliable indicator of the tendency of said surface to be hemocompatible.As a general rule, known to those skilled in the art of biomedicalengineering, the lower the level of fibrinogen adsorption onto amaterial, the higher the hemocompatibility of that material.

TABLE 3 Relative levels of fibrinogen adsorption on test surfaces asmeasured in vitro by the frequency shift of a quartz microbalance(Q-sense) Fibrinogen adsorption Item Test material (relative units) 1Stainless Steel, SS2343 83 2 PET (Dacron) 179 3 poly(DTE-carbonate) 1584 poly(I₂DTE-carbonate) 133 5 poly(76% DTE-co-24% DT-carbonate) 125 6poly(I₂DTE-co-2.5% PEG2000-carbonate) 100 7 poly(I₂DTE-co-3.4%PEG2000-carbonate) 72

In reference to TABLE 3, item 1 (stainless steel) represents aclinically used material, which is known for its low level ofthrombogenicity and its good hemocompatibility. Stainless steel servesas a control and has an acceptable level of fibrinogen adsorption. Item2 in TABLE 3 is Dacron, a known thrombogenic material which has onlylimited clinical utility in vascular applications. Dacron has thehighest level of fibrinogen adsorption of all test materials. Item 3 ispoly(DTE carbonate), the base material among the polymers represented byFormula I. Its high level of fibrinogen adsorption indicates that thispolymer is not a promising candidate for use in a blood-contactingmedical device. Either incorporation of iodine alone (Item 4) orincorporation of DT Units alone (Item 5) tend to reduce the level offibrinogen adsorption.

The foregoing demonstrates that the simultaneous incorporation ofiodine, DT, and PEG results in a major reduction in fibrinogenadsorption—at PEG levels that are still compatible with the need toprovide a mechanically strong polymer. Within this general regimen,applicants now provide yet another unexpected observation: Comparison ofitems 6 and 7 shows that a very small, incremental increase in theamount of PEG within the polymer composition can have a non-obvious andnon-predictable effect on protein adsorption. Fibrinogen adsorption topolymer composition 6 is sufficiently low to qualify this composition asa promising candidate material for use in less thrombogenic applicationswhile as little as 0.9 mol % of additional PEG added to polymercomposition 7 provided a polymer composition which appears to besuperior in terms of its hemocompatibility to the clinically usedstainless steel.

Polymer composition 7 in TABLE 3 illustrates another key designprinciple recognized for the first time by the applicants: When iodineand PEG are incorporated concomitantly into a polymer compositioncovered by Formula I, a very low molar ratio of PEG is sufficient toreduce dramatically the level of fibrinogen surface adsorption. Incombination with the previously described effect of iodine and PEG onthe mechanical properties of the polymer composition, applicants havediscovered a method to simultaneously optimize both the mechanical andbiological properties of polymers. Accordingly, the level ofthrombogenicity (i.e., increased and decreased affinity for blood cellsand proteins and other molecules related to thrombus formation) can beengineered into the embolotherapy product by varying the relative levelsof iodine and percent PEG, DT and DTE.

In addition the embolotherapy products may be delivered or be coatedwith other biocompatible bioresorbable polymers predetermined to promotebiological responses in the embolized body lumen desired for certainclinical effectiveness. The coating may be selected from the broad classof any biocompatible bioresorbable polymer which may include any one orcombination of includes use of tyrosine-derived polycarbonates,tyrosine-derived polyarylates, polyesteramides, polyamide carbonates,trimethylene carbonate, polycaprolactone, polydioxane,polyhydroxybutyrate and polyhydroxyvalerate, poly-glycolide,polylactides and stereoisomers and copolymers thereof for anybiocompatible bioresorbable polymer for instance glycolide/lactidecopolymers. The coating may act to attract and/or inhibit biologicalresponses.

In one example, the bulk of the embolotherapy product, in this example aparticle, may be comprised of a high percentage of PEG in the iodinatedpolycarbonate composition to allow a desired particle compressibilityand elasticity for localized delivery through a catheter. Further theparticle may comprise a fibrinogen absorbing coating such as chitosan orpoly(DTE carbonate) for desired thrombus formation. Such particles maybe generated by any methods and techniques known to those skilled in theart for instance standard powder coating methods used in thepharmaceutical industry, by top coating methods used in the medicaldevice industry which may use drug dryers and spray coaters and dipcoaters and the like.

Examples of such methods and techniques are disclosed in: Ravina et al.,“Arterial Embolization to Treat Uterine Myomata,” Lancet, 346, 671-672(Sep. 9, 1995); Hilal et al., “Therapeutic percutaneous embolization forextra-axial vascular lesions of the head, neck, and spine,” J.Neurosurg. 43(3), 275-287 (1975); Solomon et al., “Chemoembolization ofhepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C,ethiodol, and polyvinyl alcohol: prospective evaluation of response andsurvival in a U.S. population,” J Vasc Interv Radiol., 10(6), 793-8 Jun.1999); Tseng et al., “Angiographic embolization for epistaxis: a reviewof 114 cases.” Laryngoscope, 108(4 Pt 1), 615-9 (April 1998); Kerber etal., “Flow-controlled therapeutic embolization: a physiologic and safetechnique,”Am. J. Roentgenol., 134(3), 557-61 (March 1980); Latchaw etal., “Polyvinyl Foam Embolization of Vascular and Neoplastic Lesions ofthe Head, Neck and Spine,” Radiology, 131, 669-679 (1978); andTadavarthy, et al., “Polyvinyl Alcohol (Ivalon) A New Embolic Material,”Am. J. Roentgenol.: Radium Therapy and Nuclear Medicine, 125, 609-616(1975).

While a number of preferred embodiments of the invention and variationsthereof have been described in detail, other modifications and methodsof use will be readily apparent to those of skill in the art.Accordingly, it should be understood that various applications,modifications and substitutions may be made of equivalents withoutdeparting from the spirit of the invention or the scope of the claims.

REFERENCES CITED

 1) 6,475,477 Radio-opaque polymer biomaterials  2) 6,358,228Vasoocclusive device including asymmetrical pluralities of fibers  3)6,337,198 Porous polymer scaffolds for tissue engineering  4) 6,319,492Copolymers of tyrosine-based polyarylates and poly(alkylene oxides)  5)6,284,862 Monomers derived from hydroxy acids and polymers preparedtherefrom  6) RE37,160 Synthesis of tyrosine derived diphenol monomers 7) 6,120,491 Biodegradable, anionic polymers derived from the aminoacid L-tyrosine  8) 6,117,157 Helical embolization coil  9) 6,103,255Porous polymer scaffolds for tissue engineering 10) 6,048,521 Copolymersof tyrosine-based polyarylates and poly(alkylene oxides) 11) 5,877,224Polymeric drug formulations 12) 5,851,508 Compositions for use inembolizing blood vessels 13) 5,670,602 Synthesis of tyrosine-deriveddiphenol monomers 14) 5,658,995 Copolymers of tyrosine-basedpolycarbonate and poly(alkylene oxide) 15) 5,587,507 Synthesis oftyrosine derived diphenol monomers 16) 5,317,077 Polyarylates containingderivatives of the natural amino acid l-tyrosine 17) 5,216,115Polyarylate containing derivatives of the natural amino acid L-tyrosine18) 5,198,507 Synthesis of amino acid-derived bioerodible polymers 19)5,099,060 Synthesis of amino acid-derived bioerodible polymers 20)4,819,637 System for artificial vessel embolization and devices for usetherewith 21) 4,441,495 Detachable balloon catheter device and method ofuse

OTHER PUBLICATIONS

-   1) Interventional Radiology, Dandlinger et al, ed., Thieme, N.Y.,    1990:295-313.-   2) “Polyvinyl Alcohol Foam Particle Sizes and Concentrations    Injectable through Microcatheters”, JVIR 1998; 9:113-115-   3) “Polyvinyl Alcohol Particle Size and Suspension Characteristics”,    American Journal of Neuroradiology June 1995; 16:1335-1343.-   4) Ravina et al., Arterial Embolization to Treat Uterine Myomata,    Lancet, Sep. 9, 1995; vol. 346, pp. 671-672.-   5) “Therapeutic percutaneous embolization for extra-axial vascular    lesions of the head, neck, and spine”, Hilal et al., J. Neurosurg.    43(3), 275-287 (1975).-   6) “Chemoembolization of hepatocellular carcinoma with cisplatin,    doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol:    prospective evaluation of response and survival in a U.S.    population.” J Vasc Interv Radiol. 1999 June; 10(6):793-8. Solomon    B, Soulen M C, Baum R A, Haskal Z J, Shlansky-Goldberg R D, Cope C.-   7) “Hydrogel embolic agents. Theory and practice of adding    radio-opacity.” Link D P, Mourtada F A, Jackson J, Blashka K,    Samphilipo M A. Invest Radiol. 1994 August; 29(8):746-51.-   8) “Angiographic embolization for epistaxis: a review of 114 cases.”    Tseng E Y, Narducci C A, Willing S J, Sillers M J., Laryngoscope.    1998 April; 108(4 Pt 1):615-9.-   9) “Supraselective embolization in intractable epistaxis: review of    45 cases.” Moreau S, De Rugy M G, Babin E, Courtheoux P, Valdazo A.,    Laryngoscope. 1998 June; 108(6):887-8.-   10) “Polyvinyl alcohol particle size and suspension    characteristics.”, Derdeyn C P, Moran C J, Cross D T, Dietrich H H,    Dacey R G Jr., AJNR Am J Neuroradiol. 1995 June-July; 16(6):1335-43.-   11) “Polyvinyl alcohol foam particle sizes and concentrations    injectable through microcatheters.”, Barr J D, Lemley T J, Petrochko    C N., J Vasc Interv Radiol. 1998 January-February; 9(1 Pt 1):113-8.-   12) “Flow-controlled therapeutic embolization: a physiologic and    safe technique.”, Kerber C W., AJR Am J Roentgenol. 1980 March;    134(3):557-61.-   13) “Polyvinyl alcohol foam: prepackaged emboli for therapeutic    embolization.”, Kerber C W, Bank W O, Horton J A., AJR Am J    Roentgenol. 1978 June; 130(6):1193-4.-   14) Interventional Radiology, Dandlinger et al, ed., Thieme, N.Y.,    1990:295-313.-   15) “Polyvinyl Alcohol Foam Particle Sizes and Concentrations    Injectable through Microcatheters”, JVIR 1998; 9:113-115.-   16) “Polyvinyl Alcohol Particle Size and Suspension    Characteristics”, American Journal of Neuroradiology June 1995;    16:1335-1343.-   17) “Biodegradable microspheres of poly(DL-lactic acid) containing    piroxicam as a model drug for controlled release via the parenteral    route.”, Lalla J K, Sapna K., J Microencapsul. 1993    October-December; 10(4):449-60.-   18) “Gelfoam embolization: a simplified technique.”, Bank W O,    Kerber C W., AJR Am J Roentgenol. 1979 February; 132(2):299-301.-   19) R. E. Latchaw, L. H. Gold: “Polyvinyl Foam Embolization of    Vascular and Neoplastic Lesions of the Head, Neck and Spine,”    Radiology, 131 (1979), 669-679.-   20) S. M. Tadavarthy, J. H. Moller, K. Amplatz: “Polyvinyl Alcohol    (Ivalon) A New Embolic Material,” American Journal of Roentgenology:    Radium Therapy and Nuclear Medicine, 125 (1975), 609-616.-   21) Kerber, C W, “Catheter therapy: fluoroscopic monitoring of    deliberate embolic occlusion.” Radiology. 1977 November;    125(2):538-40.-   22) Horak, et al., “Hydrogels in endo-vascular embolization. IV.    Effect of radiopaque spherical particles on the living tissue.”    Biomaterials 9, 367-371, 1988.-   23) Horak, D et al. “Hydrogels in endovascular embolization. III.    Radiopaque spherical particles, their preparation and properties.”    Biomaterials 8, 142-145, 1987.

What is claimed is:
 1. An embolotherapy suspension product forembolizing a body lumen, comprising particles of a biocompatible,bioresorbable polymer, optionally including stereoisomers thereof, in apharmaceutically acceptable liquid, wherein the polymer particles havean excluded diameter of about 10 microns to about 3,000 microns, whereinthe embolotherapy product is radiopaque by virtue of halogen in thepolymer, and wherein said polymer comprises multiple units of Formula(II):

wherein X for each polymer unit is independently Br or I, Y is between 1and 4, inclusive and R₄ is an alkyl group with up to 18 carbon atoms andfrom 0 to 8 heteroatoms selected from O and N, or R₄ has the structure:

wherein R₅ and R₆ are each independently selected from hydrogen andalkyl groups having up to 18 carbon atoms and from 0 to 8 heteroatomsselected from O and N, and each R₉ independently has the structure:

wherein R₇ is selected from the group consisting of —CH═CH—, —CHJ₁-CHJ₂-and [[(—CH₂-)_(a)]](—CH₂-)_(a), wherein R₈ is selected from the groupconsisting of —CH═CH—, —CHJ₁-CHJ₂- and (—CH₂-)_(n)[[(—CH₂-)_(n)]],wherein a and n are independently between 0 and 8 inclusive; and J₁ andJ₂ are independently Br or I; and Q is selected from the groupconsisting of hydrogen, a free carboxylic acid group, and carboxylicacid esters and amides, wherein said esters and amides are selected fromthe group consisting of esters and amides of alkyl and alkylaryl groupscontaining up to 18 carbon atoms and esters and amides of biologicallyand pharmaceutically active compounds; wherein the polymer particleshape is selected from the group consisting of spherical andgeometrically non-uniform, wherein the particles are solid, hollow orporous; and wherein said polymer is copolymerized with a poly(C₁-C₄alkylene glycol), which is present in a weight fraction of less thanabout 75 wt %.
 2. The embolotherapy product of claim 1, wherein all Xgroups are ortho-directed with respect to the phenolic oxygen and Y is 1or
 2. 3. The embolotherapy product of claim 1, wherein R₄ is an alkylgroup.
 4. The embolotherapy product of claim 1, wherein R₉ for at leastone unit comprises a pendant —COOR₁ group, wherein, for each unit inwhich it is present, the sub-group R₁ is independently a hydrogen or analkyl group ranging from 1 to about 18 carbon atoms containing from 0 to5 heteroatoms selected from O and N.
 5. The embolotherapy product ofclaim 1, wherein each R₉ independently has the structure:

wherein R_(5a) is an alkyl group containing up to 18 carbon atoms andfrom 0 to 5 heteroatoms selected from O and N; and wherein n is aninteger from 1 to 8 inclusive; and R₁ is independently a hydrogen or analkyl group ranging from 1 to about 18 carbon atoms containing from 0 to5 heteroatoms selected from O and N.
 6. The embolotherapy product ofclaim 1, wherein each R₉ independently has the structure:

wherein a and n are independently an integer from 1 to 8, inclusive, andR₁ is independently a hydrogen or an alkyl group ranging from 1 to about18 carbon atoms containing from 0 to 5 heteroatoms selected from O andN.
 7. The embolotherapy product of claim 1, wherein said poly(C₁-C₄alkylene glycol) is poly(ethylene glycol).
 8. The embolotherapy productof claim 1, wherein between about 0.01 and about 0.99 percent of saidpolymer units comprise a pendant —COOH group.
 9. The embolotherapyproduct of claim 1, wherein said polymer further comprises an effectiveamount of at least one therapeutic agent.
 10. The embolotherapy productof claim 9, wherein said at least one therapeutic agent is selected fromthe group consisting of a chemotherapeutic agent, a non-steroidalanti-inflammatory, or a steroidal anti-inflammatory.
 11. Theembolotherapy suspension product of claim 1, further comprising aneffective amount of a radiopacifying agent, selected from the groupconsisting of iodine, bromine, barium, bismuth, gold, platinum,tantalum, tungsten, and mixtures thereof.